Portal de Periódicos da CAPES

Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes

1990; Elsevier BV; Volume: 29; Issue: 3 Linguagem: Inglês

10.1016/0028-3908(90)90001-8

1873-7064

Dennis J. McKenna, David B. Repke, Lindsay A. Lo, Stephen J. Peroutka,

Receptor Mechanisms and Signaling

Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(−)DOI in the cortex of the rat. Most derivatives displayed 2–10 times lower affinity at the HT2B receptor labelled by [3H]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 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B 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 N,N-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-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(−)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents.