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Vol. 283, Issue 1, 216-225, 1997

The Pharmacological Characterization of a Novel Selective 5-Hydroxytryptamine1A Receptor Antagonist, NAD-299

Lars Johansson, Daniel Sohn, Seth-Olof Thorberg, David M. Jackson, Diana Kelder, Lars-Gunnar Larsson, Lucy Rényi, Svante B. Ross, Carin Wallsten, Håkan Eriksson, Ping-Sheng Hu, Eva Jerning, Nina Mohell and Anita Westlind-Danielsson

Departments of Medicinal Chemistry (L.J., D.S., S.-O.T.), Behavioural and Biochemical Pharmacology (D.M.J., D.K., L.-G.L., L.R., S.B.R., C.W.) and Molecular Pharmacology (H.E., P.-S.H., E.J., N.M., A.W.-D.), Preclinical R & D, Astra Arcus AB, S151 85 Södertälje, Sweden

The pharmacological properties of a novel selective 5-hydroxytryptamine1A (5-HT1A) 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-HT1A 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-HT1A receptors in vitro with a Ki value of 0.6 nM. The only other receptors for which NAD-299 had affinity less than 1 µM were alpha-1 and beta adrenoceptors with Ki values of 260 and 340 nM, respectively. Thus, the selectivity of NAD-299 for 5-HT1A receptors was more than 400 times. WAY-100635 had considerably higher affinity than NAD-299 for alpha-1 adrenoceptors (Ki = 45 nM) and dopamine D2 and D3 receptors (Ki = 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-HT1A receptor antagonists in vitro and also behaved as such in in 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.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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