Structural determinants of 5-HT 1A versus 5-HT 1D receptor binding site selectivity

Abstract

A structure-activity analysis was used to identify selective 5-HT 1A versus 5-HT 1D receptor agents. An analysis of published data identified 13 drugs which display nanomolar affinity for the 5-HT 1A receptor and that have been analyzed at 5-HT 1D receptor binding sites. Four agents display ⩾100-fold selectivity for the 5-HT 1A receptor. Two structural features were identified which hypothetically result in selectivity for 5-HT 1A versus 5-HT 1D binding sites. The linkage of an indole ring to a basic nitrogen atom via the 4 position on the indole ring or the absence of an indole ring are two features which lower the affinity for the 5-HT 1D receptor, but do not necessarily lower the affinity for the 5-HT 1A receptor. A series of 7 agents (5 indoles, 2 quinolines) was identified which met these hypothetical selectivity criteria. These compounds were then analyzed in radioligand binding studies. These 7 agents display affinities of 1.3 - 170 nM for the 5-HT 1A receptor binding site, and 1 800 – 13 000 nM for the 5-Ht 1D receptor binding site. All 7 agents display ⩾47-fold selectivity for the 5-HT 1A versus 5-HT 1D site and 4 of the agents are > 100-fold selective. Compound No. 1 (N,N′-bis[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-menthane) and compound No. 2 (N 8-[3-(4-indolyloxy)-2-hydroxypropyl]-N 1-(propioloyl)-(Z)-1,8-diamino-p-menthane) are the most selective agents yet described for 5-HT 1A versus 5-HT 1D receptor binding sites. Moreover, compound No. 1 displays agonist activity in inhibiting forskolin-stimulated adenylate cyclase activity in rat hippocampus, while compound No. 2 antagonizes the effect of 8-OH-DPAT on 5-HT 1A-mediated adenylate cyclase activity in the system. These data indicate that a comparative structure-activity analysis can be an effective technique for the identification of potent and selective receptor agents.