EFFECTS OF SELECTIVE H5-HT1B (SB-216641) AND H5-HT1D (BRL-15572) RECEPTOR LIGANDS ON GUINEA-PIG AND HUMAN 5-HT-AUTORECEPTORS AND 5-HT-HETERORECEPTORS

Human cerebral cortical slices and synaptosomes, guinea-pig cerebral c ortical slices and human right atrial appendages were used to study th e effects of SB-216641, a preferential h5-HT1B receptor ligand, and of BRL-15572, a preferential h5-HT1D receptor ligand, on the presynaptic h5-HT1B and h5-HT1B-like autoreceptors in the human and guinea-pig br ain preparations, respectively, and on the presynaptic h5-HT1D heteror eceptors in the human atrium. The brain preparations, preincubated wit h [H-3]serotonin ([H-3]5-HT), and the segments of atrial appendages, p reincubated with [H-3]noradrenaline, were superfused with modified Kre bs' solution and tritium overflow was evoked electrically (human and g uinea-pig cerebral cortex slices and human atrial appendages) or by hi gh K+ (human cerebral cortex synaptosomes). The electrically evoked tr itium overflow from guineapig cerebral cortex slices was reduced by th e 5-HT receptor agonist 5-carboxamidotryptamine (5-CT). This effect wa s not modified by BRL-15572 (2 mu M; concentration 154 times higher th an its K-i at h5-HT1D receptors) but was antagonized by SB-216641 (0.1 mu M; concentration 100 times higher than its K-i at h5-HT1B receptor s; apparent pA(2) 8.45). SB-216641 (0.1 mu M) by itself facilitated, w hereas BRL-15572 (2 mu M) did not affect, the evoked overflow. In huma n cerebral cortex slices SB-216641 (0.1 mu M) also facilitated, and BR L-15572 (2 mu M) again failed to affect, the electrically evoked triti um overflow. In human cerebral cortical synaptosomes, 5-CT reduced the K+-evoked tritium overflow. This response was unaffected by BRL-15572 (300 nM) but antagonized by SB-216641 (15 nM; drug concentrations 23 and 15 times higher than their K-i at h5-HT1D and h5-HT1B receptors, r espectively). Both drugs, given alone, did not modify the K+-evoked tr itium overflow. In human atrial appendages, the electrically evoked tr itium overflow was inhibited by 5-HT in a manner susceptible to antago nism by BRL-15572 (300 nM; 23 times K-i at h5-HT1D receptors) but not by SB-216641 (30 nM; 30 times K-i at h5-HT1B receptors). Both drugs by themselves did not change the electrically evoked tritium overflow. I n conclusion, SB-216641 behaves as a preferential antagonist at native human 5-HT1B receptors and BRL-15572 as a preferential antagonist at native human 5-HT1D receptors. These compounds are clearly useful tool s for the differentiation between human 5-HT1B and 5-HT1D receptors in functional studies.