title: The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist.
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-HT(1A) receptor ligand with a K(i) 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-HT(7) receptor (K(i) = 240 nM). NAE-086 inhibited VIP-stimulated adenylyl cyclase activity in GH(4)ZD10 cells with 79% of the efficacy of 5-HT. This inhibition was blocked by the 5-HT(1A) receptor (and beta-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-HT(1A) receptor (K(i) = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT(1A) 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-HT(1A) syndrome (flat body posture and forepaw treading), inhibited the cage-leaving response, and caused hypothermia. All the responses mediated by postsynaptic 5-HT(1A) receptors were attenuated after single or repeated treatment of the rats with NAE-086. Simultaneously with the development of the tolerance to 5-HT(1A) receptor-mediated responses, 5-HT(2A) 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.
authors.affiliation: Local Discovery, AstraZeneca R&D Södertälje, Södertälje, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Rënyi
authors.forename: J L
authors.initials: JL
authors.lastname: Evenden
authors.forename: C J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: E
authors.initials: E
authors.lastname: Jerning
authors.forename: D
authors.initials: D
authors.lastname: Kelder
authors.forename: D
authors.initials: D
authors.lastname: Lake-Bakaar
authors.forename: L G
authors.initials: LG
authors.lastname: Larsson
authors.forename: N
authors.initials: N
authors.lastname: Mohell
authors.forename: M
authors.initials: M
authors.lastname: Sällemark
authors.forename: S B
authors.initials: SB
authors.lastname: Ross
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000009:adverse effects / Q000494:pharmacology*; D003345:Corticosterone / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012472:Salivation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: C441623:3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide; D001578:Benzopyrans; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D014316:Tritium; D012701:Serotonin; D014660:Vasoactive Intestinal Peptide; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; D006916:5-Hydroxytryptophan; D000242:Cyclic AMP; D004298:Dopamine; D003345:Corticosterone