The Pharmacological Characterization of a Novel Selective 5-Hydroxytryptamine1A Receptor Antagonist, NAD-299
- Lars Johansson1,
- Daniel Sohn1,
- Seth-Olof Thorberg1,
- David M. Jackson2,
- Diana Kelder2,
- Lars-Gunnar Larsson2,
- Lucy Rényi2,
- Svante B. Ross2,
- Carin Wallsten2,
- Håkan Eriksson3,
- Ping-Sheng Hu3,
- Eva Jerning3,
- Nina Mohell3 and
- Anita Westlind-Danielsson3
- Departments of 1Medicinal Chemistry (L.J., D.S., S.-O.T.),2Behavioural and Biochemical Pharmacology (D.M.J., D.K., L.-G.L., L.R., S.B.R., C.W.) and 3Molecular Pharmacology (H.E., P.-S.H., E.J., N.M., A.W.-D.), Preclinical R & D, Astra Arcus AB, S151 85 Södertälje, Sweden
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 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.
Footnotes
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Send reprint requests to: Dr Svante B. Ross, Behavioural and Biochemical Pharmacology, Preclinical R & D, Astra Arcus AB, S-151 85 Södertälje, Sweden.
- Abbreviations:
- DA
- dopamine
- DOPA
- l-3,4-dihydroxyphenylalanine
- 8-OH-DPAT
- 8-hydroxy-2-(di-n-propylamino)tetralin
- 5-HT
- 5-hydroxytryptamine
- IBMX
- 3-isobutyl-1-methylxanthine
- 5-HTP
- 5-hydroxytryptophan
- NAD-299
- (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate
- NSD 1015
- 3-hydroxybenzylhydrazine dihydrochloride
- (S)-UH-301
- (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin
- VIP
- vasoactive intestinal peptide
- WAY-100135
- N-tert-butyl-3-(4-(2-methoxyphenyl)piperacine-1-yl)-2-phenylpropanamide dihydrochloride
- WAY-100635
- N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride
- CHO
- Chinese hamster ovary
- FCS
- fetal calf serum
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- EDTA
- ethylenediaminetetraacetic acid
- ANOVA
- analysis of variance
- AMPA
- dl-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
- DHA
- dihydroalprenolol
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- TBPS
- tert-butylbicyclophosphothionate
- QNB
- l-quinuclidinyl benzilate
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- Received December 31, 1996.
- Accepted June 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
