| 1,2-Diarylethylamine | |
|---|---|
| Drug class | |
 1,2-Diphenylethylamine, theparent structure of most of the 1,2-diarylethylamines | |
| Class identifiers | |
| Synonyms | 1,2-Diphenylethylamines |
| Use | Research chemicals; some as designer drugs |
| Mode of action | Dissociative |
| Mechanism of action | Antagonist |
| Biological target | NMDA receptor |
| Chemical class | Arylalkylamine |
| Legal status | |
| In Wikidata | |
1,2-Diarylethylamines are a class ofpsychoactive compounds defined by twoaryl groups attached to adjacentcarbon atoms on anethylamine backbone.[1] These compounds display a range of pharmacological activities, most notably asNMDA receptor antagonists, and have attracted attention asdissociativedesigner drugs that produce feelings of detachment from reality or oneself.[2]
The synthesis ofdiphenidine reported as far back as 1924 by Christiaen.[3] Theparent structure of the class,1,2-diphenylethylamine was first synthesized in the 1940s and showed weakanalgesic activity.[4]
However it was not until the early 2010s that 1,2-diarylethylamines gained prominence as dissociative designer drugs. This shift occurred following legislative controls onarylcyclohexylamines (such asketamine andphencyclidine analogues) in the United Kingdom in 2013, which prompted the introduction of diphenidine and related compounds likemethoxphenidine (MXP) andephenidine to the grey market as "legal highs" or "research chemicals".[1]
1,2-Diarylethylamines contain the substructureArCH2CH(Ar')NRR', where Ar, Ar' =aryl and R, R' = H ororganyl.[1]
Achiral center exists at the ethylamine carbon atom bearing the two aryl groups. Theenantiomers often have a large difference in pharmacological activity. For example, (+)-(S)-diphenidine has 40 times higher affinity than (−)-(R)-form for theNMDA receptor.[3]
According to a review byJason Wallach and Simon Brandt (2018),[1] most psychoactive 1,2-diarylethylamines reported in the scientific literature contain non-heteroaromatic aryl groups (i.e., both rings arecarbocyclic). An exception islanicemine, which features a heteroaromaticpyridyl ring.[2] Additional heteroaromatic analogues have been disclosed in the patent literature.[5]
1,2-Diarylethylamines primarily antagonizeNMDA receptors, leading to dissociative effects like those ofketamine orphencyclidine (PCP). Many also interact withdopamine/norepinephrine transporters (DAT/NET) andsigma receptors, contributing to stimulant or hallucinogenic properties.[2]
| Compound | NMDAR (Ki, nM) | NET (Ki, nM) | DAT (Ki, nM) | SERT (Ki, nM) |
|---|---|---|---|---|
| Diphenidine (DPH) | 29 | 3,104 | 274 | 13,514 |
| (+)-(S)-DPH | 18 | – | – | – |
| (−)-(R)-DPH | 4,960 | – | – | – |
| 2-MXP | 103 | 6,900 | 3,858 | 15,000 |
| Ephenidine | 162 | 841 | 379 | >10,000 |
1,2-Diarylethylamines exert their primary effects asuncompetitive antagonists of the N-methyl-D-aspartate receptor (NMDAR), similar tophencyclidine (PCP) andketamine. This mechanism is believed to underlie their characteristic dissociative, hallucinogenic, and anesthetic properties. Compounds such asdiphenidine,methoxphenidine (MXP), andephenidine display high to moderate affinity for the NMDAR PCP-binding site (e.g., diphenidine Ki ≈ 18–39 nM). Additionally, some members of this class exhibit secondary interactions with monoamine transporters, including the dopamine and norepinephrine transporters (DAT and NET), as well as modest binding to sigma-1 and sigma-2 receptors, serotonin 5-HT2A receptors, alpha-adrenergic receptors, and the kappa opioid receptor. Despite potent NMDAR binding, several compounds exhibit reduced in vivo potency, potentially due to pharmacokinetic factors.[1]
1,2-Diarylethylamines are generallylipophilic, allowing for extensivetissue distribution, particularly inadipose tissue. For example, diphenidine has been found at concentrations exceeding 11,000 ng/g in fat tissue during postmortem analysis. These compounds are typically active via oral andparenteral routes, with exposure ranging from 3 to 8 hours depending on the compound and dosage. Metabolism primarily occurs via hepaticcytochrome P450 enzymes, includingCYP1A2,CYP2B6,CYP2C9,CYP2C19, andCYP3A4, leading tohydroxylated,dealkylated, andoxidized metabolites.Phase II conjugation processes such asglucuronidation andsulfation also occur. Metabolites are excreted in urine and have been detected in both clinically and in forensic settings.[1]
A number of 1,2-diarylethylamines have been explored in pharmaceutical research. Clinical analogs such aslanicemine (AZD6765) andremacemide have shown potential in the treatment ofdepression,epilepsy, andneurodegenerative diseases. Diphenidine and ephenidine have been used in animal models to investigate NMDAR-mediated neurophysiological processes, includingsynaptic plasticity andlong-term potentiation. The unique pharmacological profiles of these compounds have also made them subjects of interest in studies ofschizophrenia andpsychosis. Despite promisingin vitro andin vivo data, no 1,2-diarylethylamines have yet achieved widespread medical approval for psychiatric oranalgesic indications.[1]
Since the early 2010s, several 1,2-diarylethylamines have emerged asnew psychoactive substances (NPS) on therecreational drug market. Compounds such as diphenidine and MXP were sold online as "research chemicals" or "legal highs," often in response to regulatory crackdowns on ketamine and arylcyclohexylamine derivatives. These substances have gained popularity among users seeking dissociative effects akin to PCP and ketamine but outside legal control. Online forums and user reports have documented a range of subjective experiences, fromeuphoria andaltered perception to confusion and dissociation. However, hospitalizations and fatalities associated with their combined use with other drugs have prompted increasing regulatory scrutiny. Their sale and use have raised concerns regarding public health, leading to bans or restrictions in several countries.[1]
Diphenidine is a dissociative substance of the 1,2-diarylethylamine class.