Dextrorphan
Dextrorphan is a morphinan-class psychoactive compound that functions as the dextrorotatory enantiomer of levorphanol and the primary active metabolite of dextromethorphan, an over-the-counter antitussive agent.[1][2] Structurally characterized by the formula C₁₇H₂₃NO, it exhibits minimal affinity for opioid receptors in contrast to its levorotatory counterpart, instead acting predominantly as a non-competitive antagonist at N-methyl-D-aspartate (NMDA) receptors.[1][3] This NMDA antagonism underlies dextrorphan's neuroprotective and anticonvulsant effects, which have been demonstrated in preclinical models of cerebral ischemia and epilepsy, positioning it as a candidate for therapeutic applications beyond cough suppression.[2][4] At higher doses, dextrorphan induces dissociative and hallucinogenic states akin to those of phencyclidine, contributing to the psychoactive potential observed with dextromethorphan abuse, particularly in individuals with rapid CYP2D6 metabolism who convert the prodrug efficiently.[5][6] Unlike dextromethorphan itself, which possesses weaker NMDA-blocking potency, dextrorphan is the more efficacious mediator of these central nervous system effects.[5]Chemical and Physical Properties
Molecular Structure and Stereochemistry
Dextrorphan possesses the molecular formula C_{17}H_{23}NO and a molar mass of 257.38 g/mol. Its structure belongs to the morphinan class of polycyclic compounds, featuring a tetracyclic core with three fused six-membered rings and a piperidine ring, a phenolic hydroxyl group at the 3-position, and an N-methyl substitution on the nitrogen atom.[7] The systematic IUPAC name is (1S,9S,10S)-17-methyl-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2(7),3,5-trien-4-ol, reflecting the specific ring fusions and substituents.[7] Stereochemically, dextrorphan is the dextrorotatory enantiomer of 3-hydroxymorphinan, also known as the dextro form of levorphanol, with the configuration designated as 9α,13α,14α. [8] This absolute configuration at the three key chiral centers (positions 9, 13, and 14) distinguishes it from the pharmacologically distinct levorotatory enantiomer, levorphanol, which exhibits opioid agonist activity whereas dextrorphan acts primarily as an NMDA receptor antagonist. The stereospecificity arises from the morphinan scaffold's rigid fused ring system, where the α orientations ensure the trans fusion at ring junctions typical of the dextromethorphan series.[9]Synthesis and Production
Dextrorphan is synthesized primarily through the O-demethylation of dextromethorphan, its O-methylated precursor, using chemical reagents such as boron tribromide (BBr₃) in dichloromethane at low temperatures (0 °C to room temperature) or hydrogen bromide.[10][11] These methods selectively cleave the 3-methoxy group to yield the 3-hydroxy-N-methylmorphinan structure of dextrorphan, often followed by purification steps like chromatography or salt formation (e.g., hydrobromide).[10] Yields for BBr₃-mediated demethylation in analog syntheses have been reported at approximately 87% over multi-step processes including protection and deprotection.[12] Alternative routes involve first N-demethylation of dextromethorphan to N-desmethyl-dextromethorphan (3-methoxy-N-normorphinan), followed by N-methylation (or deuteromethylation for labeled compounds) and subsequent O-demethylation.[11][13] This stepwise approach facilitates isotopic labeling for pharmacokinetic studies, with reagents like iodomethane-d₃ (CD₃I) used for N-alkylation under basic conditions.[10] Industrial-scale production of dextrorphan is not established, as it lacks widespread therapeutic approval and is mainly accessed endogenously via CYP2D6-mediated metabolism of dextromethorphan.[1] Laboratory-scale synthesis supports research into prodrugs and derivatives, such as conjugation with oxoacids or polyethylene glycols for improved bioavailability.[14]Pharmacology
Pharmacodynamics
Dextrorphan functions primarily as a low-affinity, uncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, blocking ion channel activation by glutamate and contributing to its dissociative and neuroprotective effects.[15] This antagonism occurs at the phencyclidine (PCP) binding site within the NMDA receptor-associated ion channel, with dextrorphan exhibiting higher potency than its parent compound dextromethorphan in inhibiting NMDA-mediated responses in neuronal preparations.[16] Such activity underlies the hallucinogenic and analgesic properties observed at supratherapeutic doses, akin to those of ketamine or phencyclidine, though dextrorphan's effects are generally milder due to its pharmacokinetic profile.[17] In addition to NMDA antagonism, dextrorphan acts as an agonist at sigma-1 receptors, which are chaperone proteins modulating calcium signaling, neurotransmitter release, and neuroprotection.[18] Binding studies in rat brain membranes demonstrate high-affinity interaction with sigma-1 sites (Ki values in the nanomolar range), potentially mediating antidepressant-like effects and contributing to the modulation of mood and cognition.[19] Dextrorphan also shows low-affinity binding to sigma-2 receptors and certain nicotinic acetylcholine receptor subtypes, though these interactions are less central to its overall pharmacodynamic profile.[19] Unlike morphinan opioids, dextrorphan possesses minimal affinity for mu-opioid receptors, with binding significantly weaker than that of its levorotatory counterpart levorphanol, rendering opioid-mediated analgesia or respiratory depression negligible at typical exposure levels. However, at high concentrations, it exhibits some interaction with kappa- and delta-opioid receptors, which may influence certain sensory effects but does not drive its primary therapeutic or recreational actions.[19] Overall, dextrorphan's pharmacodynamics emphasize non-opioidergic mechanisms, distinguishing it from classical analgesics and aligning its effects more closely with dissociative agents.[16]Pharmacokinetics
Dextrorphan exhibits a plasma elimination half-life of 1.7 to 5.4 hours following intravenous administration in patients with acute stroke.[20] This range aligns with reports of a 3- to 5-hour half-life in general pharmacokinetic profiles.[15] The compound displays a large volume of distribution, approximately 300 L, reflecting extensive penetration into tissues including the central nervous system.[20] When formed as the primary metabolite of orally administered dextromethorphan, dextrorphan achieves plasma concentrations comparable to those from direct administration, indicating efficient systemic availability post-absorption and first-pass metabolism.[21] Hepatic metabolism predominates, with dextrorphan undergoing N-demethylation primarily via CYP3A4 and CYP2D6 to form 3-methoxymorphinan and other downstream metabolites, followed by glucuronidation through enzymes such as UGT2B15.[22][23] Elimination occurs mainly renally, with the bulk excreted as conjugated metabolites and negligible amounts of unchanged dextrorphan in urine.[24] Clearance details remain limited in non-epileptic populations, though dose-linear increases in exposure (AUC and Cmax) have been observed in epileptic patients receiving dextromethorphan, suggesting proportional handling of the metabolite.[25]Metabolism and Relation to Dextromethorphan
Biotransformation Pathways
Dextrorphan is generated from dextromethorphan primarily through O-demethylation at the 3-position, a reaction catalyzed by the cytochrome P450 isoform CYP2D6, which exhibits genetic polymorphism influencing conversion efficiency.[4][26] In extensive metabolizers, this pathway predominates, yielding dextrorphan as the major active metabolite with rapid hepatic processing.[27] Following formation, dextrorphan undergoes N-demethylation at the 17-position, mainly mediated by CYP3A4, to produce 3-hydroxymorphinan, a secondary metabolite excreted primarily via urine after further conjugation.[22][28] CYP2D6 contributes to a lesser extent in this step, highlighting CYP3A4's dominant role in dextrorphan's clearance.[22] Dextrorphan also undergoes phase II glucuronidation at the 3-hydroxy group, facilitated by uridine diphosphate glucuronosyltransferase enzymes including UGT2B15, enhancing solubility and renal elimination with urinary recovery exceeding 80% of administered doses within 48 hours in typical subjects.[26][28] These pathways collectively determine dextrorphan's short plasma half-life of approximately 1.2–2.2 hours.[29]Comparative Activity
Dextrorphan demonstrates markedly higher potency as a noncompetitive antagonist at N-methyl-D-aspartate (NMDA) receptors compared to dextromethorphan, its prodrug precursor. In vitro binding studies indicate a Ki value of approximately 200 nM for dextrorphan at NMDA receptor sites, versus 3,500 nM for dextromethorphan, reflecting roughly 17-fold greater affinity for dextrorphan.[30] This differential contributes to dextrorphan's primary role in mediating the dissociative and neuroprotective effects observed following dextromethorphan administration, as the metabolite achieves higher brain concentrations in extensive metabolizers via CYP2D6-mediated O-demethylation.[5][17] In contrast, dextromethorphan exhibits superior binding affinity at sigma-1 receptors, with a Kd of 57 nM compared to 400 nM for dextrorphan, suggesting dextromethorphan's direct involvement in sigma-1-mediated antitussive, neuroprotective, and potential antidepressant actions independent of extensive metabolism.[30] Dextromethorphan also inhibits serotonin reuptake (SERT) with moderate potency (Ki ≈ 23–240 nM), an effect less pronounced in dextrorphan, which aligns with dextromethorphan's role in modulating monoaminergic systems.[18]| Receptor/Target | Dextromethorphan Ki/Kd (nM) | Dextrorphan Ki/Kd (nM) | Notes |
|---|---|---|---|
| NMDA | 3,500 | 200 | Noncompetitive antagonism; dextrorphan more potent.[30] |
| Sigma-1 | 57 | 400 | Dextromethorphan higher affinity.[30] |
| α3β4* Nicotinic | Higher potency | One-third potency of DXM | Dextrorphan weaker blocker.[31] |