title: The pharmacological characterization of a novel selective 5-hydroxytryptamine1A receptor antagonist, NAD-299.
abstract: 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 microM 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 micromol/kg s.c., depending on the test and the dose of 8-hydroxy-2-(di-n-propylamino)tetralin.
authors.affiliation: Department of Medicinal Chemistry, Preclinical R & D, Astra Arcus AB, Södertälje, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Johansson
authors.forename: D
authors.initials: D
authors.lastname: Sohn
authors.forename: S O
authors.initials: SO
authors.lastname: Thorberg
authors.forename: D M
authors.initials: DM
authors.lastname: Jackson
authors.forename: D
authors.initials: D
authors.lastname: Kelder
authors.forename: L G
authors.initials: LG
authors.lastname: Larsson
authors.forename: L
authors.initials: L
authors.lastname: Rényi
authors.forename: S B
authors.initials: SB
authors.lastname: Ross
authors.forename: C
authors.initials: C
authors.lastname: Wallsten
authors.forename: H
authors.initials: H
authors.lastname: Eriksson
authors.forename: P S
authors.initials: PS
authors.lastname: Hu
authors.forename: E
authors.initials: E
authors.lastname: Jerning
authors.forename: N
authors.initials: N
authors.lastname: Mohell
authors.forename: A
authors.initials: A
authors.lastname: Westlind-Danielsson
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D004295:Dihydroxyphenylalanine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan; C108607:robalzotan; D003345:Corticosterone