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Cholinergic

The term "cholinergic" is derived from "choline," a nutrient abundant in bile (from Greek khole "bile"), combined with the suffix "-ergic" from Greek ergon "work," reflecting acetylcholine's role in physiological actions.^[1] The cholinergic system is a fundamental neurotransmitter pathway in the nervous system, primarily involving the synthesis, release, and signaling of acetylcholine (ACh), the endogenous agonist for cholinergic receptors, which mediates neurotransmission in the autonomic nervous system, somatic motor system, and central nervous system (CNS).^[2] ACh is synthesized from choline and acetyl-coenzyme A by the enzyme choline acetyltransferase (ChAT) and is rapidly degraded by acetylcholinesterase (AChE) to terminate its action, ensuring precise temporal control of signaling.^[3] This system is essential for maintaining physiological homeostasis, particularly through the parasympathetic branch of the autonomic nervous system, where it promotes "rest and digest" responses such as slowing heart rate, stimulating glandular secretions, and enhancing gastrointestinal motility.^[2] Cholinergic signaling occurs via two main receptor classes: nicotinic receptors, which are ligand-gated ion channels that facilitate fast synaptic transmission at neuromuscular junctions (N1 subtype) and in autonomic ganglia and the CNS (N2 subtype), enabling rapid excitatory effects like muscle contraction and neuronal depolarization; and muscarinic receptors, which are G-protein-coupled receptors (subtypes M1–M5) that mediate slower, modulatory responses in smooth muscles, cardiac tissue, glands, and the CNS.^[2] In the brain, cholinergic neurons originating from the basal forebrain and brainstem project widely to regions like the cortex, hippocampus, and thalamus, where ACh acts as a neuromodulator to enhance attention, learning, and memory formation by promoting synaptic plasticity, such as long-term potentiation, and regulating neuronal excitability and network synchronization.^[4] Beyond cognition, the system influences broader functions including cerebral blood flow regulation, neuroprotection against inflammation via the cholinergic anti-inflammatory pathway, and even non-neuronal roles in immune modulation.^[3] Dysfunctions in cholinergic transmission are implicated in various disorders, including Alzheimer's disease—where degeneration of basal forebrain cholinergic neurons contributes to cognitive decline—and conditions like myasthenia gravis, schizophrenia, and autonomic neuropathies, underscoring its therapeutic targeting with cholinesterase inhibitors and receptor agonists.^[4]^[2]

Definition and Overview

Etymology and Basic Definition

The term "cholinergic" was coined by the British pharmacologist Sir Henry Hallett Dale in the early 1930s to describe nerve fibers or tissues that function through the chemical transmitter acetylcholine, distinguishing them from adrenergic fibers that use adrenaline (epinephrine).^[5]^[6] Dale introduced the term alongside "adrenergic" to emphasize the chemical basis of neurotransmission rather than anatomical origins, building on his pioneering work identifying acetylcholine as a neurotransmitter in 1914.^[7] Etymologically, "cholinergic" derives from "choline"—a precursor molecule in acetylcholine synthesis, itself from Greek khole ("bile"), reflecting its discovery in bile in 1862—and the suffix "-ergic," from Greek ergon ("work"), indicating activation or function by a specific agent.^[1]^[8] In its basic definition, "cholinergic" pertains to any biological process, neuron, synapse, or tissue involving acetylcholine (ACh), the primary neurotransmitter of the parasympathetic nervous system and certain central nervous system pathways.^[9] Tissues or cells responsive to acetylcholine, or those that liberate, synthesize, or are activated by it, are termed cholinergic, encompassing roles in signal transduction across somatic, autonomic, and central neural systems.^[10] This includes preganglionic sympathetic and parasympathetic neurons, as well as postganglionic parasympathetic fibers, where acetylcholine mediates excitatory or inhibitory effects via specific receptors.^[11] The cholinergic system broadly supports functions such as muscle contraction, glandular secretion, heart rate regulation, and cognitive processes like attention and memory.^[12]

Physiological Roles

The cholinergic system, mediated by the neurotransmitter acetylcholine (ACh) and its receptors, plays pivotal roles in regulating diverse physiological processes across the central and peripheral nervous systems. In the central nervous system (CNS), cholinergic signaling is fundamental to cognitive functions, including attention, learning, and memory formation, primarily through muscarinic receptors (M1, M4, M5) that facilitate synaptic plasticity in regions like the hippocampus and cerebral cortex.^[2] Nicotinic receptors (N2 subtype) further contribute by modulating neuronal growth, survival, differentiation, and the release of other neurotransmitters such as dopamine and ACh itself, supporting overall brain development and function.^[2] In the peripheral nervous system (PNS), the cholinergic system governs autonomic and somatic activities. At the neuromuscular junction, nicotinic receptors (N1 subtype) enable the transmission of signals from motor neurons to skeletal muscles, converting electrical impulses into mechanical contractions essential for voluntary movement.^[2] Within the autonomic nervous system, particularly the parasympathetic branch, muscarinic receptors (M2 and M3) mediate the "rest and digest" response: M2 receptors in the heart decrease heart rate by enhancing potassium conductance via vagal innervation, while M3 receptors promote glandular secretions, gastrointestinal motility, and bronchoconstriction to support digestion and respiratory adjustments.^[2]^[12] Beyond the nervous systems, cholinergic signaling influences cardiovascular regulation and immune responses. Muscarinic receptors on the endothelium of blood vessels in skeletal muscle mediate vasodilation by stimulating nitric oxide release, which relaxes vascular smooth muscle and helps to modulate blood pressure, while in immune cells, activation of nicotinic receptors—upregulated during T-cell stimulation—dampens inflammation and cytokine release, contributing to anti-inflammatory effects.^[12]^[13] During embryonic development, both receptor types guide CNS organization, including cell migration and synapse formation, underscoring the system's broad homeostatic importance.^[2]

Cholinergic Neurotransmission

Synthesis and Release of Acetylcholine

Acetylcholine (ACh) is synthesized in the presynaptic terminals of cholinergic neurons through a single-step enzymatic reaction involving the precursors choline and acetyl coenzyme A (acetyl-CoA).^[14] This process is catalyzed by the enzyme choline acetyltransferase (ChAT), which is highly concentrated in the nerve terminals and exhibits a Michaelis constant (K_m) of approximately 1 mM for choline and 10 μM for acetyl-CoA.^[14] ChAT is synthesized in the neuronal cell body and transported axonally to the terminals, where it facilitates the rapid production of ACh to meet release demands.^[11] The availability of choline, the rate-limiting substrate, is primarily ensured by high-affinity, sodium-dependent uptake via the choline transporter (CHT1) at the presynaptic membrane, with a K_m of 1-5 μM.^[14] Choline is sourced from extracellular fluid, dietary intake, or recycling from the hydrolysis of previously released ACh by acetylcholinesterase in the synaptic cleft.^[15] Acetyl-CoA is generated from glucose metabolism through pyruvate oxidation in neuronal mitochondria, and its production can be upregulated by increased neuronal activity via calcium-dependent mechanisms.^[11] The synthesis rate is thus tightly regulated by substrate availability and neuronal firing, ensuring efficient ACh production without accumulation of precursors.^[14] Once synthesized, ACh is rapidly transported into synaptic vesicles by the vesicular acetylcholine transporter (VAChT), a proton-dependent antiporter that exchanges vesicular H⁺ for cytoplasmic ACh, driven by a vacuolar H⁺-ATPase.^[14] Each vesicle typically stores around 2,000 ACh molecules in the central nervous system, along with ATP and proteoglycans as counterions, forming a quantal unit for release.^[14] Vesicular uptake is inhibited by vesamicol with an IC₅₀ of 40 nM, highlighting the specificity of this packaging mechanism.^[14] ACh release occurs via calcium-dependent exocytosis triggered by action potential invasion of the presynaptic terminal.^[11] Depolarization opens voltage-gated calcium channels, allowing Ca²⁺ influx that promotes the docking, fusion, and fission of vesicles with the presynaptic membrane, releasing quanta of approximately 10,000 ACh molecules at central synapses.^[15] This process follows the SNARE complex-mediated fusion pathway, with spontaneous miniature releases occurring at rest and evoked releases synchronized to neuronal activity.^[11] Newly synthesized ACh is preferentially mobilized from a readily releasable pool, while a reserve pool replenishes vesicles during sustained activity.^[14]

Degradation and Reuptake Mechanisms

Acetylcholine (ACh) is rapidly degraded in the synaptic cleft primarily by the enzyme acetylcholinesterase (AChE), which hydrolyzes it into choline and acetate to terminate neurotransmission and prevent overstimulation of cholinergic receptors.^[9] AChE operates with exceptional efficiency, catalyzing the breakdown of up to 5,000 ACh molecules per second per enzyme molecule, owing to its structural features including a deep, narrow active-site gorge approximately 20 Å long and 5 Å wide.^[16] The catalytic mechanism involves the binding of ACh to the catalytic anionic site (CAS) via cation-π interactions with aromatic residues such as Trp86, followed by nucleophilic attack from the catalytic triad (Ser203, His447, Glu334 in human AChE), which forms an acyl-enzyme intermediate; deacylation then occurs with water assistance, releasing the products.^[16] This process is facilitated by the enzyme's α/β hydrolase fold, an oxyanion hole that stabilizes the transition state, and dynamic motions of the gorge periphery that allow substrate entry and product exit.^[16] Butyrylcholinesterase (BChE), a related enzyme, also contributes to ACh degradation but at a slower rate and primarily in non-neuronal tissues or under conditions of AChE inhibition; it shares structural similarities with AChE but has a broader substrate specificity.^[17] The degradation products, particularly choline, are not simply diffused away but are efficiently recycled through reuptake mechanisms to support sustained ACh synthesis in cholinergic neurons.^[9] Following hydrolysis, choline is reuptaken into presynaptic cholinergic terminals via the high-affinity choline transporter 1 (CHT1, encoded by SLC5A7), a sodium- and chloride-coupled symporter that represents the rate-limiting step for ACh replenishment.^[18] CHT1 operates with a 2 Na⁺:1 Cl⁻:1 choline stoichiometry, utilizing the electrochemical gradient of sodium to drive uphill transport against concentration gradients, achieving an affinity (Km) around 1-5 μM for choline.^[19] Structurally, CHT1 features 13 transmembrane helices forming a LeuT-fold core, with choline binding centrally stabilized by cation-π interactions from aromatic residues (e.g., Trp62, Tyr91) and hydrogen bonding; chloride enhances affinity by coordinating the choline hydroxyl group.^[19] This transporter is densely localized on presynaptic membranes and traffics activity-dependently to synaptic vesicles, ensuring choline availability correlates with neuronal firing rates.^[20] Inhibition of CHT1, such as by hemicholinium-3, profoundly reduces cholinergic transmission by limiting choline recycling, underscoring its essential role in maintaining synaptic ACh levels.^[19] Unlike many neurotransmitters, ACh itself lacks a direct reuptake transporter and relies entirely on enzymatic degradation followed by precursor recycling for termination and renewal.^[9]

Cholinergic Receptors

Nicotinic Receptors

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that mediate fast excitatory neurotransmission in response to the endogenous agonist acetylcholine (ACh) and exogenous ligands like nicotine.^[21] These receptors belong to the Cys-loop superfamily of ion channels and are crucial components of the cholinergic system, facilitating rapid signal transduction across synapses.^[22] Upon agonist binding, nAChRs undergo conformational changes that open a central cation-selective pore, permitting influx of Na⁺, K⁺, and in some cases Ca²⁺ ions, leading to membrane depolarization and downstream physiological effects.^[23] The structural architecture of nAChRs consists of five transmembrane subunits arranged pseudosymmetrically around a water-filled pore, each subunit featuring a large extracellular N-terminal domain (ECD) for ligand binding, four membrane-spanning helices (M1–M4), and an intracellular C-terminal domain.^[21] The ECD contains the orthosteric binding sites at subunit interfaces, typically involving principal (e.g., α subunits) and complementary components.^[22] High-resolution cryo-electron microscopy (cryo-EM) structures, such as those of the Torpedo muscle-type nAChR at 4 Å resolution, have revealed the molecular basis of gating, showing how agonist binding twists the ECD to rearrange the transmembrane domain and dilate the pore from ~3 Å to ~8 Å. More recent atomic-level models (e.g., human α4β2 at 3.9 Å) highlight allosteric sites in the transmembrane domain that modulate channel function, including positive allosteric modulators like PNU-120596 that stabilize open states in α7 subtypes.^[23] nAChRs are classified into two primary categories based on subunit composition and location: muscle-type and neuronal-type. Muscle-type nAChRs predominate at the postsynaptic membrane of the neuromuscular junction (NMJ), where they are heteropentamers composed of two α1, one β1, one δ, and one ε subunit in adult skeletal muscle (fetal form substitutes γ for ε).^[22] These receptors exhibit low Ca²⁺ permeability (P_Ca/P_Na ≈ 0.1) and mediate the endplate potential essential for skeletal muscle contraction, with a high density of ~10,000 receptors per μm² at the NMJ.^[21] In contrast, neuronal nAChRs are more diverse, assembled from α2–α10 and β2–β4 subunits (with α5 and β3 as accessories), forming either homopentamers (e.g., α7 or α9) or heteropentamers (e.g., α4β2, α3β4).^[22] They display varied biophysical properties, such as the high Ca²⁺ permeability (P_Ca/P_Na ≥10) of α7 homomers, which enable rapid desensitization and Ca²⁺-dependent signaling.^[21] Physiologically, muscle-type nAChRs are specialized for reliable, high-fidelity transmission at the NMJ, ensuring coordinated muscle activation; disruptions, as in myasthenia gravis, lead to impaired neuromuscular signaling due to autoantibodies reducing receptor density.^[22] Neuronal nAChRs, distributed widely in the central nervous system (e.g., hippocampus, ventral tegmental area) and peripheral autonomic ganglia, function presynaptically to enhance neurotransmitter release (e.g., dopamine via α4β2 in reward pathways) and postsynaptically to modulate excitability and plasticity.^[21] For instance, α7 nAChRs in the hippocampus contribute to synaptic plasticity underlying learning and memory, while α3β4 subtypes in sensory ganglia influence pain signaling.^[23] Unlike muscle receptors, neuronal subtypes often operate at lower agonist concentrations and exhibit slower kinetics, supporting modulatory rather than purely transmissive roles in cholinergic circuits.^[22] Seminal studies, beginning with the isolation of nAChRs from Torpedo electric organs using α-bungarotoxin in the 1970s, paved the way for cloning of subunits in the 1980s and structural elucidation in the 2000s.^[22] The crystal structure of acetylcholine-binding protein (AChBP) in 2001 provided the first ECD model, informing subsequent full receptor structures. Advances in cryo-EM since 2015 have yielded numerous high-resolution nAChR structures, revealing subtype-specific allosteric mechanisms, such as lipid-binding sites that influence gating in muscle receptors and desensitization pathways in neuronal α7.^[23] As of 2025, additional high-resolution structures, including those of human α7 nAChR in various functional states, have further elucidated desensitization and recovery mechanisms.^[24] These insights underscore the evolutionary conservation of nAChRs from invertebrates to mammals, with neuronal forms showing greater diversity to accommodate complex integrative functions in the cholinergic system.^[22]

Muscarinic Receptors

Muscarinic receptors are a class of G protein-coupled receptors (GPCRs) that bind acetylcholine and mediate many of the parasympathetic nervous system's effects, as well as certain central nervous system functions.^[25] They exhibit a seven-transmembrane domain structure typical of class A GPCRs, with orthosteric binding sites for acetylcholine and allosteric sites that allow for selective modulation.^[26] Five subtypes, designated M1 through M5 and encoded by the CHRM1 to CHRM5 genes, have been identified, each with distinct tissue distributions, signaling pathways, and physiological roles.^[26] The subtypes differ in their G protein coupling and downstream effects. M1, M3, and M5 receptors couple to Gq/11 proteins, activating phospholipase C to produce inositol trisphosphate (IP3) and diacylglycerol (DAG), which increase intracellular calcium and protein kinase C activity, leading to excitatory responses such as smooth muscle contraction and glandular secretion.^[25] In contrast, M2 and M4 receptors couple to Gi/o proteins, inhibiting adenylyl cyclase to decrease cyclic AMP levels and activating potassium channels, resulting in inhibitory effects like cardiac slowing.^[25] All subtypes can also engage β-arrestin-dependent pathways for prolonged signaling, particularly in processes like insulin secretion via M3.^[26] Distribution of muscarinic receptors varies across tissues, reflecting their diverse functions. M1 receptors predominate in the cerebral cortex, hippocampus, and autonomic ganglia, contributing to cognition, learning, and neuronal excitation.^[25] M2 receptors are abundant in the heart (atria and sinoatrial node), presynaptically modulating neurotransmitter release and reducing heart rate.^[25] M3 receptors are found in smooth muscle of the airways, gastrointestinal tract, bladder, and in exocrine glands, driving bronchoconstriction, peristalsis, micturition, and salivation.^[25] M4 receptors localize mainly to the central nervous system, including the hippocampus and striatum, where they regulate dopamine release and motor control.^[26] M5 receptors, the least understood, are expressed in the substantia nigra and hypothalamus, influencing dopamine modulation and potentially reward pathways.^[26] Pharmacologically, muscarinic receptors are targets for both agonists and antagonists with varying subtype selectivity. Non-selective agonists like pilocarpine and carbachol mimic acetylcholine to stimulate glandular secretion and smooth muscle contraction, used clinically for glaucoma and urinary retention.^[27] Selective M1 agonists, such as xanomeline, enhance cognition and are investigated for Alzheimer's disease.^[27] Antagonists include atropine, a non-selective agent that blocks all subtypes to treat bradycardia and reduce secretions, and subtype-specific ones like darifenacin (M3-selective) for overactive bladder and tiotropium (M3-selective) for chronic obstructive pulmonary disease.^[25] Recent advances focus on allosteric modulators and bitopic ligands to achieve greater selectivity, minimizing side effects in treating schizophrenia (M1/M4 positive allosteric modulators) and other disorders.^[26]

Cholinergic Drugs

Agonists

Cholinergic agonists are pharmacological agents that mimic the action of acetylcholine (ACh), the primary neurotransmitter in the cholinergic system, by either directly binding to and activating cholinergic receptors or indirectly potentiating endogenous ACh signaling. These drugs are classified into direct-acting and indirect-acting categories based on their mechanism of action. Direct agonists bind specifically to muscarinic or nicotinic ACh receptors, eliciting receptor-specific responses, while indirect agonists, primarily cholinesterase inhibitors, increase ACh availability by preventing its enzymatic degradation.^[28] Direct-acting muscarinic agonists primarily target M3 receptors in smooth muscle and glands, producing effects such as increased glandular secretions, smooth muscle contraction, and reduced intraocular pressure. Choline esters like bethanechol selectively stimulate muscarinic receptors in the bladder and gastrointestinal tract, making it useful for treating postoperative urinary retention and non-obstructive urinary retention by enhancing detrusor muscle contraction without significant nicotinic effects. Pilocarpine, a natural alkaloid, is widely used topically in ophthalmology to treat glaucoma by constricting the pupil and facilitating aqueous humor drainage, thereby lowering intraocular pressure; it also stimulates salivation for xerostomia management in Sjögren's syndrome. Cevimeline, a synthetic analog, similarly activates muscarinic receptors to increase salivary flow and is approved for dry mouth associated with Sjögren's syndrome. These agents can cause adverse effects like bradycardia, hypotension, diarrhea, and bronchoconstriction due to widespread muscarinic activation, particularly in overdose scenarios.^[28] Direct-acting nicotinic agonists activate ionotropic nicotinic ACh receptors (nAChRs), which are ligand-gated cation channels involved in fast synaptic transmission at neuromuscular junctions, autonomic ganglia, and the central nervous system. Nicotine, a prototypical full agonist, binds to α4β2 and α7 nAChRs, leading to dopamine release in reward pathways and enhanced attention and cognition in some contexts; however, its addictive potential limits therapeutic use. Varenicline, a partial agonist at α4β2 nAChRs, produces submaximal activation (about 30-60% of nicotine's effect) while competitively antagonizing nicotine binding, reducing craving and withdrawal symptoms; it is FDA-approved for smoking cessation, achieving 44% abstinence rates at 9-12 weeks compared to 18% with placebo. Other partial agonists like cytisine, derived from plants, function similarly for smoking cessation and have been used in Europe with comparable efficacy to varenicline but lower cost. In dementia, such as Alzheimer's disease (AD), nAChR agonists like ABT-089 (partial agonist) and AZD3480 (full agonist) have shown modest improvements in attention and working memory in phase II trials, though broader cognitive benefits remain inconsistent. Safety profiles for nicotinic agonists generally include mild nausea, dizziness, and insomnia, with rare neuropsychiatric events for varenicline; they are better tolerated than full agonists like nicotine.^[29] Indirect-acting cholinergic agonists, or cholinesterase inhibitors, reversibly or irreversibly block acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh, thereby prolonging its synaptic action. Reversible inhibitors like donepezil, rivastigmine, and galantamine are centrally acting and approved for mild-to-moderate AD under the cholinergic hypothesis, which posits ACh deficiency in the disease; they modestly improve cognition and daily functioning, with donepezil slowing decline by 2-3 months in meta-analyses. Neostigmine and pyridostigmine, peripherally acting due to quaternary structure, treat myasthenia gravis by enhancing neuromuscular transmission, increasing muscle strength in 60-80% of patients. Irreversible inhibitors, such as organophosphates (e.g., echothiophate for glaucoma), are used sparingly due to toxicity risks like the SLUDGE syndrome (salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis). Common adverse effects include gastrointestinal upset, bradycardia, and muscle cramps, often managed by dose titration.^[28]^[29] Recent advances in cholinergic agonists emphasize selective receptor targeting to minimize side effects. For instance, selective M1 muscarinic agonists, such as xanomeline-trospium (KarXT, approved by the FDA in September 2024 as Cobenfy), combine orthosteric agonism with peripheral antagonism to treat schizophrenia symptoms by enhancing prefrontal cholinergic signaling without dopamine blockade; pivotal phase III trials (EMERGENT-2 and EMERGENT-3) reported significant reductions in Positive and Negative Syndrome Scale scores compared to placebo. These developments highlight a shift toward subtype-specific agonists for neurological disorders, improving therapeutic indices over non-selective agents.^[29]^[30]

Antagonists

Cholinergic antagonists, also known as anticholinergics or parasympatholytics, are pharmacological agents that inhibit the actions of acetylcholine (ACh) by binding to and blocking cholinergic receptors, thereby reducing parasympathetic nervous system activity. These drugs are classified based on the receptor subtype they target: muscarinic antagonists, which block G-protein-coupled muscarinic receptors (M1-M5), and nicotinic antagonists, which block ligand-gated ion channel nicotinic receptors found at autonomic ganglia and the neuromuscular junction. By competitively antagonizing ACh binding, these agents disrupt cholinergic neurotransmission, leading to effects such as increased heart rate, reduced glandular secretions, and relaxation of smooth muscles.^[31] Muscarinic antagonists primarily counteract parasympathetic effects by inhibiting ACh at muscarinic receptors distributed throughout the central and peripheral nervous systems. For instance, blockade of M2 receptors in the heart increases heart rate and atrioventricular conduction, while M3 receptor antagonism in smooth muscles and glands reduces bronchoconstriction, gastrointestinal motility, and salivary secretions. Common examples include atropine, a natural alkaloid derived from belladonna plants, which is used for its broad-spectrum muscarinic blockade; ipratropium, a synthetic quaternary ammonium compound effective in respiratory conditions due to its poor blood-brain barrier penetration; and scopolamine, often employed for its central effects in motion sickness. Clinically, these agents are indicated for conditions such as chronic obstructive pulmonary disease (COPD) to induce bronchodilation (e.g., ipratropium via inhalation at 17 mcg per puff, up to four times daily), organophosphate poisoning to reverse excessive muscarinic stimulation (e.g., atropine 2-5 mg IV, titrated as needed), and postoperative nausea or urinary incontinence. Adverse effects commonly include dry mouth, blurred vision from mydriasis, constipation, urinary retention, and tachycardia, with central effects like confusion in elderly patients due to M1 receptor blockade; contraindications encompass narrow-angle glaucoma, acute myocardial infarction, and myasthenia gravis.^[31] Nicotinic antagonists target ionotropic nicotinic ACh receptors (nAChRs), which are pentameric channels mediating fast synaptic transmission. These are further divided into those acting at the neuromuscular junction (NmJ) and autonomic ganglia. Non-depolarizing neuromuscular blockers, such as rocuronium and vecuronium (steroidal agents) or atracurium and cisatracurium (benzylisoquinolinium compounds), competitively bind to postsynaptic nAChRs at the NmJ, preventing depolarization and causing flaccid paralysis without initial fasciculations. They are essential in anesthesia for facilitating endotracheal intubation and maintaining muscle relaxation during surgery, with rocuronium typically dosed at 0.6 mg/kg IV for rapid sequence induction. Prolonged effects can occur in hypothermia, renal impairment, or with potentiators like aminoglycosides, and reversal is achieved using cholinesterase inhibitors like neostigmine alongside muscarinic antagonists to mitigate side effects. Ganglionic blockers, such as mecamylamine or historical agents like hexamethonium, non-selectively inhibit nAChRs in both sympathetic and parasympathetic ganglia, leading to widespread autonomic blockade, hypotension from vasodilation and reduced cardiac output, and inhibition of ganglionic transmission. Due to their non-specific effects causing impotence, constipation, dry mouth, and cycloplegia, ganglionic blockers are rarely used today, limited to investigational roles in smoking cessation or obsolete hypertension management.^[32]^[33] Overall, the therapeutic utility of cholinergic antagonists hinges on their selectivity and route of administration to minimize off-target effects, with muscarinic agents dominating clinical practice while nicotinic blockers remain niche due to risks of paralysis or autonomic instability. Recent advances focus on subtype-selective antagonists, such as M3-specific agents for overactive bladder (e.g., darifenacin), to enhance efficacy and reduce adverse events.^[31]

Structure-Activity Relationships

The structure-activity relationships (SAR) of direct-acting cholinergic agonists are centered on mimicking the key pharmacophore of acetylcholine, which consists of an ester linkage between a quaternary ammonium group and an acetyl moiety separated by an ethylene bridge. The acetyl group is optimal for activity; replacement with longer chains like propionyl or butyryl reduces potency due to steric hindrance at the receptor binding site.^[34] The ethylene bridge (two-carbon chain) is essential, as extensions to three or more carbons diminish activity, while α-methyl substitution enhances nicotinic selectivity and potency, as seen in acetyl-α-methylcholine, whereas β-methyl substitution favors muscarinic activity, exemplified by methacholine, where the S-enantiomer matches acetylcholine's potency and the R-enantiomer is 20-fold less active.^[34] The quaternary ammonium group is critical for muscarinic receptor activation, with smaller alkyl substituents like methyl preferred; larger groups such as ethyl render compounds inactive. Replacement of the ester with ether or ketone linkages yields stable analogs like carbachol, which resists cholinesterase hydrolysis while retaining potent muscarinic agonism. For muscarinic selectivity, carbamate esters like carbachol demonstrate enhanced stability and gastrointestinal activity compared to acetylcholine. Non-ester alkaloids such as pilocarpine maintain activity through a structurally distinct but pharmacophoric mimicry of the onium head and hydrogen-bonding elements.^[34]^[28] In contrast, SAR for muscarinic antagonists (anticholinergics) emphasize a bulky, hydrophobic framework to block the orthosteric site, typically featuring a tertiary or quaternary amine basic center linked via an ester or ether to a carbocyclic or heterocyclic ring system. The basic center requires small alkyl substitutions (methyl, ethyl, or isopropyl) for optimal protonation and binding; quaternary forms enhance antagonist potency. An ester linkage boosts activity but can be replaced by ethers, as in orphenadrine, without loss of efficacy. Bulky groups at R2 and R3 positions, such as phenyl or cyclohexyl rings, are vital for hydrophobic interactions, maximizing blockade, while a 2-4 carbon connecting bridge optimizes chain flexibility, with two carbons providing peak activity in compounds like dicyclomine.^[35] Classic examples include atropine and scopolamine, tropane alkaloids where the esterified tropic acid moiety and quaternary tropanium nitrogen confer high muscarinic affinity and selectivity over nicotinic receptors; modifications like epimerization at C-6 in scopolamine increase CNS penetration due to reduced polarity. For nicotinic antagonists, such as non-depolarizing neuromuscular blockers like pancuronium, bis-quaternary ammonium structures with steroid or piperazinium cores separated by a 10-12 atom chain are key, enabling competitive blockade at the neuromuscular junction; shortening the chain reduces potency by altering receptor fit. Selectivity challenges arise from receptor homology, with orthosteric antagonists often lacking subtype specificity, prompting allosteric approaches for targeted muscarinic blockade, as informed by crystal structures of M2 and M3 receptors bound to antagonists like tiotropium.^[35]^[36]

Clinical and Pathological Aspects

Cholinergic Hypothesis of Alzheimer's Disease

The cholinergic hypothesis of Alzheimer's disease (AD) posits that a selective deficiency in cholinergic neurotransmission, particularly due to degeneration of basal forebrain cholinergic neurons, contributes significantly to the cognitive impairments characteristic of the disorder. This theory emerged from early observations in the 1970s demonstrating reduced levels of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis, in postmortem brain tissues from AD patients compared to age-matched controls. Specifically, studies reported up to 90% loss of ChAT activity in the hippocampus and neocortex, regions critical for memory and learning, correlating with the severity of dementia.^[37]^[38] Pathological evidence supporting the hypothesis centers on the degeneration of cholinergic neurons in the basal forebrain, including the nucleus basalis of Meynert (nbM), which provides major cholinergic innervation to the cerebral cortex and hippocampus. Autopsy examinations have revealed a 70-80% reduction in these neurons in AD brains, with neuronal atrophy and loss preceding widespread amyloid plaque and tau tangle formation in some cases. In vivo imaging studies using PET tracers for vesicular acetylcholine transporter (VAChT) further confirm early cholinergic denervation in prodromal AD stages, associating it with episodic memory deficits and progression to mild cognitive impairment. Neurochemical analyses also show decreased ACh release and upregulated muscarinic receptors as compensatory responses, underscoring the system's vulnerability.^[39]^[40]^[41] The hypothesis gained prominence through influential reviews that integrated these findings, proposing cholinergic dysfunction as a key driver of age-related memory decline in AD. Pharmacological validation came from animal models where scopolamine-induced anticholinergic blockade mimicked AD-like cognitive deficits, reversible by cholinomimetics. Clinically, this led to the development of acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine, which modestly enhance cognition by increasing synaptic ACh levels; meta-analyses indicate 2-3 point improvements on the Alzheimer's Disease Assessment Scale-cognitive subscale in mild-to-moderate AD. However, limitations include the hypothesis's incomplete explanation of non-cognitive symptoms and its integration with amyloid and tau pathologies, prompting ongoing research into multi-target therapies.^[42]

Role in Other Disorders

The cholinergic system plays a prominent role in Parkinson's disease (PD), where degeneration of cholinergic neurons in the nucleus basalis of Meynert and pedunculopontine nucleus contributes to both motor and non-motor symptoms.^[43] This degeneration is evident through reduced acetylcholinesterase activity in cortical and thalamic regions, as shown by PET and SPECT imaging studies.^[43] Cognitively, cholinergic loss correlates with executive dysfunction, visuospatial impairments, and dementia, affecting up to 75% of PD patients after 10 years.^[43] Motorically, it exacerbates postural instability, gait disorders, and falls, with postmortem analyses revealing greater pedunculopontine nucleus neuron loss in fall-prone individuals.^[43] Non-motor features, including olfactory deficits (in 95% of cases), depression, apathy, and REM sleep behavior disorder, are also linked to these deficits.^[43] Therapeutically, cholinesterase inhibitors like rivastigmine have shown modest benefits in cognition and gait, supporting targeted cholinergic enhancement.^[43]^[44] In schizophrenia, cholinergic dysfunction manifests as reduced densities of muscarinic M1/M4 and nicotinic α4β2/α7 receptors in brain regions such as the prefrontal cortex, hippocampus, and striatum, contributing to cognitive and psychotic symptoms.^[45] Postmortem studies confirm decreased choline acetyltransferase activity in the septum and nucleus accumbens, alongside sensory gating deficits tied to α7 nicotinic receptor hypofunction.^[45] Antimuscarinic agents like scopolamine can induce schizophrenia-like psychosis, underscoring the system's role in dopaminergic imbalance.^[45] Clinically, acetylcholinesterase inhibitors such as galantamine improve processing speed and attention in trials involving up to 86 patients over 12 weeks.^[45] Emerging therapies target these receptors, with M1/M4 agonists like xanomeline demonstrating antipsychotic effects in preclinical models.^[45] Cholinergic hyperactivity is implicated in major depressive disorder, where elevated central acetylcholine levels correlate with melancholic features, including anhedonia and psychomotor retardation.^[46] Acetylcholinesterase inhibitors like physostigmine exacerbate depressive symptoms and increase immobility in forced swim tests in rodents, while altering REM sleep and cortisol responses in humans.^[46] Muscarinic M1 receptor antagonism, as with scopolamine (4 μg/kg IV), induces rapid antidepressant effects, achieving 56% remission rates within 3 days in treatment-resistant cases, sustained for over 15 days.^[46] Nicotinic receptors, particularly α7 and β2 subtypes in the prefrontal cortex and hippocampus, modulate mood; partial agonists like varenicline show promise in augmenting antidepressants.^[46] These findings support cholinergic modulation as a fast-acting therapeutic avenue.^[46] Myasthenia gravis involves autoimmune targeting of postsynaptic nicotinic acetylcholine receptors at the neuromuscular junction, leading to impaired synaptic transmission and fluctuating muscle weakness. Circulating autoantibodies reduce receptor density by up to 70-90%, blocking acetylcholine binding and accelerating receptor internalization. This peripheral cholinergic disruption primarily affects ocular, bulbar, and limb muscles, with thymic abnormalities present in 80% of cases. Some evidence suggests central cholinergic involvement, with cognitive deficits observed in subsets of patients, though results are inconsistent across studies.^[47] Treatments like pyridostigmine enhance acetylcholine availability, but excessive dosing risks cholinergic crisis, mimicking myasthenic exacerbation with muscarinic and nicotinic overstimulation.^[48]

Therapeutic Applications and Recent Advances

Cholinergic drugs are primarily employed in the management of conditions involving deficient cholinergic neurotransmission, with cholinesterase inhibitors serving as the cornerstone for symptomatic treatment in Alzheimer's disease (AD). These agents, including donepezil, rivastigmine, and galantamine, enhance acetylcholine levels by inhibiting its breakdown, thereby improving cognitive function in mild to moderate AD patients.^[28] Clinical guidelines recommend their initiation in early stages, with efficacy monitored at 3- and 6-month intervals, though they do not alter disease progression.^[28] In neuromuscular disorders, indirect agonists like pyridostigmine are first-line for myasthenia gravis, augmenting acetylcholine at the neuromuscular junction to alleviate muscle weakness.^[28] Neostigmine, another cholinesterase inhibitor, is used for reversing non-depolarizing neuromuscular blockade post-surgery and treating postoperative urinary retention or acute colonic pseudo-obstruction.^[28] Direct muscarinic agonists, such as bethanechol, address neurogenic bladder dysfunction by stimulating detrusor muscle contraction.^[28] Ophthalmic applications leverage direct agonists like pilocarpine and carbachol to lower intraocular pressure in open-angle glaucoma through miosis and enhanced aqueous humor outflow.^[28] Cevimeline, a selective muscarinic agonist, treats xerostomia in Sjögren's syndrome by promoting salivary secretion.^[28] Rivastigmine extends to Parkinson's disease dementia, where it mitigates cognitive decline by bolstering cholinergic activity in affected brain regions.^[28] Recent advances in cholinergic therapeutics emphasize personalized modulation and novel agents. In AD, the 2024 drug pipeline includes IVL3003, a next-generation cholinesterase inhibitor in phase 2 trials, aimed at enhancing cognitive outcomes with potentially improved tolerability.^[49] KarXT (xanomeline-trospium), a muscarinic M1/M4 agonist, is advancing in phase 3 for neuropsychiatric symptoms, offering a non-dopaminergic approach to agitation and cognition via selective cholinergic activation.^[49] Ongoing trials of donepezil in phase 1 and 3 continue to explore optimized dosing for broader efficacy.^[49] In Parkinson's disease (PD), longitudinal imaging studies using [18F]FEOBV PET have identified three cholinergic subgroups—hypercholinergic (29%), mixed (41%), and hypo-cholinergic (30%)—correlating with motor, gait, and cognitive phenotypes.^[50] Hypo-cholinergic profiles predict severe postural instability and gait difficulties, suggesting subgroup-specific therapies like targeted cholinesterase inhibitors could refine treatment.^[50] These findings, from a 2025 multicenter study, highlight compensatory cholinergic upregulation in early PD, paving the way for precision interventions.^[50]

References

[1]
Physiology, Cholinergic Receptors - StatPearls - NCBI Bookshelf - NIH
Cholinergic receptors function in signal transduction of the somatic and autonomic nervous systems. The receptors are named because they become activated by the ...Bookshelf · Function · PathophysiologyMissing: neuroscience | Show results with:neuroscience
[2]
Cholinergic System and Its Therapeutic Importance in Inflammation ...
The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and ...
[3]
The cholinergic system in the pathophysiology and treatment of ...
The cholinergic system is important for neuronal function in memory, learning, and other essential aspects of cognition and plays a wider role in the promotion ...
[4]
Sir Henry Dale (1875–1968) - PMC - NIH
Mar 27, 2024 · Dale used the words 'cholinergic' and 'adrenergic' to designate nerve fibres by the nature of the chemical, going beyond the anatomical ...
[5]
Henry Hallett Dale - Mayo Clinic Proceedings
Dale coined the terms cholinergicand adrenergicto empha- size the chemical transmitter of the nerve rather than its anatomical origin. He also discovered ...
[6]
The Nobel Chronicles - The Lancet
In 1914, he suggested that acetylcholine was probably the “most suitable chemical” for parasympathetic neurotransmission. He coined such terms as “cholinergic” ...
[7]
Cholinergic - Etymology, Origin & Meaning
from choline, name of a basic substance abundant in bile (coined in German, 1862, from Greek khole "bile;" see cholera) + Greek ergon "work"
[8]
cholinergic, adj. meanings, etymology and more | Oxford English ...
cholinergic is formed within English, by compounding. Etymons: choline n., ‑ergic suffix. See etymology. Nearby entries. cholesterol-lowering, adj.1956 ...
[9]
Physiology, Acetylcholine - StatPearls - NCBI Bookshelf
Tissues of the body that use this chemical messenger or are responsive to it are referred to as cholinergic.
[10]
CHOLINERGIC Definition & Meaning - Merriam-Webster
Oct 24, 2025 · The meaning of CHOLINERGIC is liberating, activated by, or involving acetylcholine. How to use cholinergic in a sentence.
[11]
Chapter 11: Acetylcholine Neurotransmission
In the autonomic nervous system, acetylcholine (ACh) is the neurotransmitter in the preganglionic sympathetic and parasympathetic neurons. These are shown in ...
[12]
Basic and modern concepts on cholinergic receptor: A review - PMC
Cholinergic system is an important system and a budding branch of autonomic nervous system which plays a vital role in memory, digestion, control of heart beat, ...
[13]
Physiological functions of the cholinergic system in immune cells
May 12, 2017 · Immunological activation of T cells up-regulates cholinergic activity, including ChAT and AChE expression. Moreover, toll-like receptor agonists ...
[14]
Synthesis, Storage and Release of Acetylcholine - NCBI - NIH
Acetylcholine is synthesized from its two immediate precursors, choline and acetyl coenzyme A. The synthesis reaction is a single step catalyzed by the enzyme ...
[15]
Acetylcholine - Neuroscience - NCBI Bookshelf - NIH
Acetylcholine is synthesized in nerve terminals from acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline, in a reaction catalyzed by ...
[16]
Acetylcholinesterase: Structure, dynamics, and interactions with ...
Sep 19, 2025 · Acetylcholinesterase (AChE) is an enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh), removing it from the synaptic cleft after ...
[17]
Protective role of acetylcholine and the cholinergic system in the ...
Sep 20, 2024 · The degradation of ACh occurs rapidly by cholinesterases, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Both AChE and ...The Cholinergic System Of... · Nachrs · Cholinesterase Inhibitors
[18]
Transport mechanism of presynaptic high-affinity choline uptake by ...
Apr 8, 2024 · In cholinergic neurons, the high-affinity choline transporter (CHT1) provides an extraordinarily efficient reuptake mechanism to reutilize ...
[19]
Structural mechanisms of human sodium-coupled high-affinity ...
Nov 26, 2024 · As a rate-limiting determinant of acetylcholine synthesis, inhibiting CHT1-mediated choline uptake can reduce cholinergic transmission function.
[20]
Discovery of Compounds that Positively Modulate the High Affinity ...
Feb 26, 2017 · The high affinity choline transporter (CHT) is responsible for uptake of choline into cholinergic nerve terminals, where it is acetylated by ...Missing: reuptake | Show results with:reuptake
[21]
Neuronal Nicotinic Acetylcholine Receptor Structure and Function ...
Mammalian nicotinic acetylcholine receptors (nAChRs) are composed on five subunits arranged around a water-filled pore (Fig. 1). ... The α8 subunit has been found ...
[22]
Muscle and neuronal nicotinic acetylcholine receptors - 2007
Jul 19, 2007 · They are formed by the assembly of five transmembrane subunits, selected from a pool of 17 homologous polypeptides (α1–10, β1–4, γ, δ, and ε).
[23]
The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs
Aug 2, 2024 · Structure and function meet at the nicotinic acetylcholine receptor-lipid interface. ... muscle-type nicotinic acetylcholine receptors.<|control11|><|separator|>
[24]
Physiology, Muscarinic Receptor - StatPearls - NCBI Bookshelf - NIH
Muscarinic receptors are G-coupled protein receptors involved in the parasympathetic nervous system. The only exception to these receptors is the sweat glands.
[25]
Muscarinic acetylcholine receptors: novel opportunities for drug ...
The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral ...Muscarinic Acetylcholine... · Targeting Machrs In Disease · Bitopic Muscarinic Ligands
[26]
Muscarinic Receptor Agonists and Antagonists - PMC
A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented.
[27]
Cholinergic Medications - StatPearls - NCBI Bookshelf - NIH
The direct-acting cholinergic agonists work by directly binding to and activating the muscarinic receptors. Examples of direct-acting cholinergic agents include ...Continuing Education Activity · Indications · Mechanism of Action · Adverse Effects
[28]
https://www.ncbi.nlm.nih.gov/books/NBK538163/
[29]
Muscarinic Antagonists - StatPearls - NCBI Bookshelf - NIH
The muscarinic antagonist is a class medication used to manage and treat numerous conditions, including COPD and organophosphate toxicity.
[30]
Neuromuscular Blockade - StatPearls - NCBI Bookshelf - NIH
Nov 13, 2023 · Nondepolarizing neuromuscular blockers are competitive acetylcholine (ACh) antagonists that bind directly to nicotinic receptors on the ...
[31]
Ganglionic Blockers - CV Pharmacology
Ganglionic blockers inhibit autonomic activity by interfering with neurotransmission within autonomic ganglia. This reduces sympathetic outflow to the heart.
[32]
[PDF] SAR (Structure activity relationship ) of directly acting cholinergic ...
❖Replacement of the hydrogen atom from the ethylene bridge by methyl group leads to equal or greater cholinergic activity. Presence of groups larger than ...
[33]
[PDF] SAR of anticholinergic drugs
SAR of anticholinergic drugs. Page 2. R2, R3 should be carbocyclic (phenyl/cyclohexyl/cyclopentyl) or heterocyclic ring for maximum antagonist activity. Ester ...
[34]
Muscarinic acetylcholine receptors: novel opportunities for drug ...
Jun 6, 2014 · The orthosteric site can provide high affinity and is supported by decades of studies of structure–activity relationships (SARs), but mAChR- ...
[35]
https://course.cutm.ac.in/wp-content/uploads/2021/03/Pages-from-Anticholinergic-drugs-3-2.pdf
[36]
https://www.nature.com/articles/nrd4295
[37]
https://doi.org/10.1016/s0140-6736(76)91936-x
[38]
https://doi.org/10.1016/s0140-6736(77)91780-9
[39]
Revisiting the Cholinergic Hypothesis in Alzheimer's Disease
Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's ...
[40]
https://doi.org/10.1002/ana.410100202
[41]
Cholinergic Dysfunction in Parkinson's Disease - PMC
There is accumulating evidence that cholinergic system degeneration not only contributes to cognitive but also to other non-motor features and motor impairments ...
[42]
Role of the Central Cholinergic System in the Therapeutics of ...
Other non-selective mAChR antagonists (e.g., Ditran) were also found to induce psychosis in normal humans and to exacerbate the symptoms of schizophrenia [68].
[43]
Cholinergic Regulation of Mood: From Basic and Clinical Studies to ...
Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate ...
[44]
Cognitive impairment as a central cholinergic deficit in patients with ...
Myasthenia Gravis has central cholinergic deficits manifested by cognitive dysfunction. · The hypothesis of Central Nervous System cholinergic involvement was ...
[45]
Cholinergic Crisis - StatPearls - NCBI Bookshelf - NIH
Apr 6, 2025 · Cholinergic crisis is a potentially life-threatening medical emergency resulting from the overstimulation of nicotinic and muscarinic receptors.
[46]
Alzheimer's disease drug development pipeline: 2024 - Cummings
Apr 24, 2024 · There are 164 trials assessing 127 drugs across the 2024 AD pipeline. There were 48 trials in Phase 3 testing 32 drugs, 90 trials in Phase 2 assessing 81 drugs ...
[47]
A multicenter longitudinal study of cholinergic subgroups in ... - Nature
Jul 1, 2025 · Three PD subgroups are identified: hypercholinergic (regional upregulation; 29%), mixed (regional upregulation and regional deficits; 40.8%) and ...