5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA).
The affinities of a series of 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA) derivatives, most of which are hallucinogenic in man, and several related agents were determined for rat cortical serotonin (5-HT) binding sites. Competition assays were performed in which these agents were competed for the 5-HT2 binding of [3H]ketanserin, or the 5-HT1 binding of [3H]LSD (in the presence of ketanserin). The R(-)-isomers of DOI, DOM and DON (i.e. the 4-iodo, -methyl and -nitro derivatives of 2,5-DMA) were found to be more potent than their racemates and demonstrated selectivity for 5-HT2 sites. These same agents in competing for [3H]ketanserin binding resulted in Hill coefficients significantly less than unity; computer-assisted analysis indicated a two-state model better fit the data. In the presence of 10(-4) M Gpp(NH)p the competition curve for R(-)-DOI produced a Hill coefficient close to unity. These results are consistent with the hypothesis that certain derivatives of 2,5-DMA, in particular R(-)-DOI, may be potent and selective agonists at 5-HT2 binding sites, sites that may constitute a serotonin receptor that is regulated by a guanine nucleotide regulatory protein. Conversely, the interactions of these agents at 5-HT1 sites was with a lower affinity and a lack of stereoselectivity. Although DOI and DOM are amongst the most potent of these agents as hallucinogens, it is still too premature to draw any conclusions regarding a possible relationship between 5-HT binding and hallucinogenic potency.
D000662:Amphetamines / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006213:Hallucinogens / Q000378:metabolism*; D066298:In Vitro Techniques; D007650:Ketanserin; D008297:Male; D008566:Membranes / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000662:Amphetamines; D006213:Hallucinogens; D010880:Piperidines; D011985:Receptors, Serotonin; D006165:Guanylyl Imidodiphosphate; D007650:Ketanserin; C036157:2,5-dimethoxyamphetamine