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 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 2-state model better fir the data. In the presence of 10-4 M Gpp(NH)p [5''-guanylimidodiphosphate] the competition curve for R(-)-DOI produced a Hill coefficient close to unity. Apparently, 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 regulated by a guanine nucleotide regulatory protein. The interactions of these agents at 5-HT1 sites was with a lower affinity and a lack of stereoselectivity. Although DOI and DOM are among 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.