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

The pharmacological properties of the 5-hydroxytryptamine (HT)(1A) receptor agonist (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-ben zopyran-5-carboxamide (NAE-086) were examined with in vitro and in vivo tec hniques. Receptor binding studies demonstrated that NAE-086 was a high-affi nity and selective 5-HT1A receptor ligand with a K-i value of 4.5 nM in mem branes from rat hippocampus. Of 32 other receptors examined NAE-086 had a m odest affinity only for the 5-HT7 receptor (K-i = 240 nM). NAE-086 inhibite d VIP-stimulated adenylyl cyclase activity in GH(4)ZD10 cells with 79% of t he efficacy of 5-HT. This inhibition was blocked by the 5-HT1A receptor (an d beta -adrenoceptor) antagonist (-)alprenolol. A minor metabolite of NAE-0 86 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 affinit y for the 5-HT1A receptor (K-i = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT1A receptor agonist in rats: it decreased 5-HT sy nthesis (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 th e 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-mediat ed responses were enhanced, as judged from the increased number of spontane ous and/or agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced wet-dog shake responses. The significance of this behavioral effect in rela tion to clinical observations is discussed.