RT Journal Article
SR Electronic
T1 The Pharmacological Characterization of a Novel Selective  5-Hydroxytryptamine<sub>1A</sub> Receptor Antagonist, NAD-299
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 216
OP 225
VO 283
IS 1
A1 Lars Johansson
A1 Daniel Sohn
A1 Seth-Olof Thorberg
A1 David M. Jackson
A1 Diana Kelder
A1 Lars-Gunnar Larsson
A1 Lucy Rényi
A1 Svante B. Ross
A1 Carin Wallsten
A1 Håkan Eriksson
A1 Ping-Sheng Hu
A1 Eva Jerning
A1 Nina Mohell
A1 Anita Westlind-Danielsson
YR 1997
UL http://jpet.aspetjournals.org/content/283/1/216.abstract
AB 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 werealpha-1 and beta adrenoceptors withKi 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 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. The American Society for Pharmacology and Experimental Therapeutics