The Pharmacological Profile of (R)-3,4-Dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine1A Receptor Agonist
- Lucy Rënyi,
- John L. Evenden1,
- Christopher J. Fowler2,
- Eva Jerning,
- Diana Kelder,
- Desmond Lake-Bakaar,
- Lars-Gunnar Larsson,
- Nina Mohell3,
- Maria Sällemark and
- Svante B. Ross
- Eva Jerning, Lead Discovery, AstraZeneca R&D, S-151 85 Södertälje, Sweden. E-mail:eva.jerning{at}astrazeneca.com
Abstract
The pharmacological properties of the 5-hydroxytryptamine (HT)1A receptor agonist (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide (NAE-086) were examined with in vitro and in vivo techniques. Receptor binding studies demonstrated that NAE-086 was a high-affinity and selective 5-HT1A receptor ligand with aKi value of 4.5 nM in membranes from rat hippocampus. Of 32 other receptors examined NAE-086 had a modest affinity only for the 5-HT7 receptor (Ki = 240 nM). NAE-086 inhibited VIP-stimulated adenylyl cyclase activity in GH4ZD10 cells with 79% of the efficacy of 5-HT. This inhibition was blocked by the 5-HT1A receptor (and β-adrenoceptor) antagonist (−)alprenolol. A minor metabolite of NAE-086 in rats, (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide had a similar receptor profile but had 17 times higher affinity for the 5-HT1A receptor (Ki = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT1A receptor agonist in rats: it decreased 5-HT synthesis (5-HTP accumulation) and 5-HT turnover (measured as the ratio of 5-hydroxyindoleacetic acid/5-HT), increased corticosterone secretion, induced the 5-HT1A syndrome (flat body posture and forepaw treading), inhibited the cage-leaving response, and caused hypothermia. All the responses mediated by postsynaptic 5-HT1A receptors were attenuated after single or repeated treatment of the rats with NAE-086. Simultaneously with the development of the tolerance to 5-HT1A receptor-mediated responses, 5-HT2A receptor-mediated responses were enhanced, as judged from the increased number of spontaneous and/or agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced wet-dog shake responses. The significance of this behavioral effect in relation to clinical observations is discussed.
Footnotes
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↵1 Present address: AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850.
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↵2 Present address: Department of Pharmacology, Umeå University, S-901 87 Umeå, Sweden.
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↵3 Present address: Acadia Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine
- ANOVA
- analysis of variance
- CCK
- cholecystokinin
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- DOI
- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
- DOPA
- l-3,4-dihydroxyphenylalanine
- DPDPE
- [d-Pen2,d-Pen5]-enkephalin
- EEDQ
- 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
- GABA
- γ-aminobutyric acid
- GH4ZD10
- rat pituitary tumor cells
- HPLC
- high-performance liquid chromatography
- 5-HIAA
- 5-hydroxyindoleacetic acid
- 5-HTP
- 5-hydroxytryptophan
- 8-OH-DPAT
- 8-hydroxy-2-(di-n-propylamino)tetralin
- NAE-084
- (S)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide
- NAE-111
- (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide
- NSD 1015
- 3-hydroxybenzylhydrazine dihydrochloride
- TBPS
- t-butylbicyclophosphorothionate
- VIP
- vasoactive intestinal polypeptide
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- Received May 16, 2001.
- Accepted August 29, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
