Pharmacology of a mixed 5-hydroxytryptamine1A/dopamine agonist

MF Piercey, AH Tang, RA Lahti, PF VonVoigtlander, PJ Schreur, RB McCall, JT Lum- Ragan, WE Hoffmann, SR Franklin and RA Code

Upjohn Company, Kalamazoo, Michigan.

U-67413B (4-hydroxydipropylaminodihydrophenalene) bound with high affinity to both 5-hydroxytryptamine (HT)1A and D2-dopamine (DA) receptor sites. U-67413B depressed 5-HT and DA cell firing rates and depressed synthesis of both neurotransmitters. The drug depressed mouse body temperatures by an amount similar to that for buspirone, gepirone and ipsapirone, but less than that for 8-hydroxy-N,N-dipropyl-2- aminotetralin. In rats, it produced the 5-HT1A behavioral syndrome. In contrast to 5-HT1A agonists having DA antagonist effects, U-67413B mildly depressed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavioral tests designed to measure anxiolytic activities, U-67413B was a slightly more effective anxiolytic than standard 5-HT1A anxiolytics (buspirone, gepirone and ipsapirone). The data are consistent with the hypothesis that effects of 5-HT1A agonists on NA neuron activity are mediated through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.

Volume 268, Issue 3, pp. 1304-1310, 03/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics