Abstract

The pharmacological properties of a novel selective 5-hydroxytryptamine_1A (5-HT_1A) receptor antagonist, NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate] were examined in vitro and in vivo and compared with the reference 5-HT_1A receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazin-yl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride]. The new compound had high affinity for 5-HT_1A receptors in vitro with a K_i value of 0.6 nM. The only other receptors for which NAD-299 had affinity less than 1 μM werealpha-1 and beta adrenoceptors withK_i values of 260 and 340 nM, respectively. Thus, the selectivity of NAD-299 for 5-HT_1A receptors was more than 400 times. WAY-100635 had considerably higher affinity than NAD-299 for alpha-1 adrenoceptors (K_i = 45 nM) and dopamine D₂ and D₃ receptors (K_i = 79 and 67 nM, respectively). Like WAY-100635, NAD-299 competitively blocked 5-HT-induced inhibition of vasoactive intestinal peptide-stimulated cAMP production in GH₄ZD10 cells and had no intrinsic activity. Both compounds were therefore 5-HT_1A receptor antagonists in vitro and also behaved as such inin vivo experiments. Thus, they competitively antagonized the 8-hydroxy-2-(di-n-propylamino)tetralin-induced 5-HT behavioral effects, hypothermia, corticosterone secretion and inhibition of passive avoidance behavior without causing any actions of their own. The effective dose of NAD-299 varied between 0.03 and 0.35 μmol/kg s.c., depending on the test and the dose of 8-hydroxy-2-(di-n-propylamino)tetralin.