Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes (original) (raw)

Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at S-HT,,, 5-HT?, and S-HT,, recognition sites, using radioligand competition studies, Nearly all of the derivatives displayed greatest potency for the 5-HT,, receptor, labelled by ['?'I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT,, receptor labelled by [)H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4-or S-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT,, site, vs the 5-HT,, site, while the 5-substituted derivatives displayed approximately equal potency at the S-HT,, and S-HT,, sites. Affinity of all the compounds at the S-HT,, site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the NJ-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT,, and S-HT,, recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines. like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT,, recognition site, labelled by [1251]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT, receptor may partially mediate the action of hallucinogenic agents.