S-14297, A NOVEL SELECTIVE LIGAND AT CLONED HUMAN DOPAMINE-D-3 RECEPTORS, BLOCKS 7-OH-DPAT-INDUCED HYPOTHERMIA IN RATS

The selective dopamine D-3 receptor agonist, 7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and the novel naphthofurane, S 14297 ((+)-17-(N,N-dipropylamino)-5,6,7,8-tetrahydro-raphtho(2,3b)dihydro,2,3-furanel) bound with high affinity and selectivity to recombinant, human dopamine D-3 versus D-2 receptors stably transfected into Chinese hamster ovary cells: K-i values = 2 versus 103 nM for 7-OH-DPAT and 13 versus 297 nM for S 14297. In contrast, the putative dopamine D-3 receptor antagonist, AJ 76 (cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin), displayed low affinity and selectivity for dopamine D-3 versus D-2 sites (70 versus 154 nM). 7-OH-DPAT (0.01-0.16 mg/kg s.c.) provoked hypothermia in rats, an action abolished by S 14297 (0.04-0.63 mg/kg s.c.) and, less potently, by AJ 76 (0.16-2.5 mg/kg s.c.). S 14297 (20.0 mg/kg s.c.) did not modify prolactin secretion. These data suggest that dopamine D-3 receptors mediate hypothermia in the rat and that S 14297 acts as a selective antagonist at these sites.