Serotonin receptor affinities of psychoactive phenalkylamine analogs

Abstract

Employing a rat fundus model, the serotonin (5-HT) receptor affinities of 45 phenalkylamine analogues were determined. Phenethylamine and phenylisopropylamine possess relatively low receptor affinities; in general, mono-, di-, and trimethoxylation enhance affinity. Of the disubstituted compounds, methoxyl groups at the 2 and 5 positions are optimal for imparting a high affinity. 4-Methylation, 4-ethylation and 4-bromination also enhance receptor affinity, while N,N-dimethylation of the terminal amine decreases affinity. alpha-Methylation of phenethylamines has little effect on affinity when racemates are examined. Introduction of a benzylic keto group can either increase or decrease affinity, depending upon the presence of other aromatic substituents. The most behaviorally active compounds were found to possess the highest 5-HT receptor affinities, while less active compounds were found to possess lower affinities.

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

“…[67] Addition of a b-methyl group to the side chain has been found to reduce in vivo activity, and this applies to b-hydroxy and b-keto groups as well. [166,167] Interestingly, certain b-methoxy-substituted phenethylamines retain some potency in humans. [117,145] The poor ability of b-oxygenated agents to cross the blood-brain barrier and enter the CNS is thought to account for the reduced in vivo activity.…”

Studies on distribution and metabolism of para-methoxymethamphetamine (PMMA) in rats after subcutaneous administration

“…Considering the pharmacological properties of structurally related phenylalkylamines with para substitution of the aromatic ring (Nichols et al, 1982;Acuna-Castillo et al, 2002;Glennon et al, 1980;Daws et al, 2000;Steele et al, 1992), it can be implied that the psychedelic effects of PMMA are mediated via serotonergic receptors in the central nervous system with the potential development of serotonin syndrome (Nichols et al, 1982;Steele et al, 1992;Green and Hait, 1980). Pharmacological discrimination studies using rats (Glennon et al, 2007;Glennon et al, 1997;Glennon et al, 1988;Glennon and Higgs, 1992) have indicated that PMMA shares significant similarities with MDMA, however, PMMA lacks the stimulant characteristics of MDMA.…”

Parallel artificial membrane permeability assay for blood–brain permeability determination of illicit drugs and synthetic analogues

“…For instance, the serotonin 5-HT2a receptor is a common target of psychoactive drugs (methamphetamine, ecstasy, psilocybin, etc.) [27,28]. Determining the affinity of new substances for this receptor would provide an additional dimension of understanding of how these substances can affect the body.…”