Vol. 299, Issue 3, 883-893, December 2001

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

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

Local Discovery, AstraZeneca R&D Södertälje, Södertälje, Sweden

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-HT₇ receptor (K_i = 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-HT_1A receptor (and -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.