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: L Rënyi, J L Evenden, C J Fowler, E Jerning, D Kelder, D Lake-Bakaar, L G Larsson, N Mohell, M Sällemark, S B Ross
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 299 Issue 3 Pg. 883-93 (Dec 2001) ISSN: 0022-3565 [Print] United States
• PMID: 11714872 (Publication Type: Journal Article)

Chemical References

• 3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide
• Benzopyrans
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists
• Tritium
• Serotonin
• Vasoactive Intestinal Peptide
• Hydroxyindoleacetic Acid
• Dihydroxyphenylalanine
• 5-Hydroxytryptophan
• Cyclic AMP
• Dopamine
• Corticosterone

Topics

• 5-Hydroxytryptophan (metabolism)
• Animals
• Behavior, Animal (drug effects)
• Benzopyrans (adverse effects, pharmacology)
• Corticosterone (metabolism)
• Cyclic AMP (metabolism)
• Dihydroxyphenylalanine (metabolism)
• Dopamine (metabolism)
• Drug Interactions
• Hydroxyindoleacetic Acid (metabolism)
• Hypothermia (chemically induced)
• Male
• Penile Erection (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Receptors, Serotonin, 5-HT1
• Salivation (drug effects)
• Serotonin (metabolism)
• Serotonin Receptor Agonists (pharmacology)
• Tritium
• Tumor Cells, Cultured
• Vasoactive Intestinal Peptide (pharmacology)