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5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA).

M Shannon, G Battaglia, Richard A Glennon, M Titeler

European Journal of Pharmacology June 15, 1984 DOI: 10.1016/0014-2999(84)90333-9 (opens in new tab)

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AI-extracted from the abstract
Characteristics In vitro binding study Peer reviewed
Population Rat cortical serotonin (5-HT) binding sites (membrane preparations)
Measures [3H]ketanserin binding, [3H]LSD binding, Hill coefficient
Topics Serotonin
Key points The R(-)-isomers of DOI, DOM and DON were more potent than their racemates and selective for 5-HT2 sites, while binding at 5-HT1 sites was lower-affinity and lacked stereoselectivity. Hill coefficients below unity at 5-HT2 sites, shifting toward unity with Gpp(NH)p, led the authors to propose that R(-)-DOI may be a potent, selective 5-HT2 agonist at a receptor regulated by a guanine nucleotide regulatory protein; they state it is premature to relate 5-HT binding to hallucinogenic potency.

Abstract

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.

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