TY - JOUR T1 - The Pharmacological Profile of (<em>R</em>)-3,4-Dihydro-<em>N</em>-isopropyl-3-(<em>N</em>-isopropyl-<em>N</em>-propylamino)-2<em>H</em>-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine<sub>1A</sub> Receptor Agonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 883 LP - 893 VL - 299 IS - 3 AU - Lucy Rënyi AU - John L. Evenden AU - Christopher J. Fowler AU - Eva Jerning AU - Diana Kelder AU - Desmond Lake-Bakaar AU - Lars-Gunnar Larsson AU - Nina Mohell AU - Maria Sällemark AU - Svante B. Ross Y1 - 2001/12/01 UR - http://jpet.aspetjournals.org/content/299/3/883.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -