THE PHARMACOLOGICAL CHARACTERIZATION OF A NOVEL SELECTIVE 5-HYDROXYTRYPTAMINE(1A) RECEPTOR ANTAGONIST, NAD-299

The pharmacological properties of a novel selective 5-hydroxytryptamin e(1A) (5-HT1A) receptor antagonist, NAD-299 [(R)-3-N, 8-fluoro-3,4-dih ydro-2H-1-benzopyran-5-carbaxamide hydrogen (2R,3R)-tartrate monohydra te] were examined in vitro and in vivo and compared with the reference 5-HT1A receptor antagonist, WAY-100635 [N-(2-(1-4-(2-methoxyphenyl)pi perazin-yl))ethyl) cyclohexanecarboxamide trihydrochloride]. The new c ompound had high affinity for 5-HT1A receptors in vitro with a K-i Val ue of 0.6 nM. The only other receptors for which NAD-299 had affinity less than 1 mu M were alpha-1 and beta adrenoceptors with K-l values o f 260 and 340 nM, respectively. Thus, the selectivity of NAD-299 for 5 -HT1A receptors was more than 400 times. WAY-100635 had considerably h igher affinity than NAD-299 for alpha-1 adrenoceptors (K-i = 45 nM) an d dopamine D-2 and D-3 receptors (K-i = 79 and 67 nM, respectively. Li ke WAY-100635, NAD-299 competitively blocked 5-HT-induced inhibition o f vasoactive intestinal peptide-stimulated cAMP production in GH(4)ZD1 0 cells and had no intrinsic activity. Both compounds were therefore 5 -HT1A receptor antagonists in vitro and also behaved as such in in viv o experiments. Thus, they competitively antagonized the 8-hydroxy-2-(d i-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-2 99 varied between 0.03 and 0.35 mu mol/kg s.c., depending on the test and the dose of 8-hydroxy-2-(di-n-propylamino)tetralin.