SB-216641 AND BRL-15572 - COMPOUNDS TO PHARMACOLOGICALLY DISCRIMINATEH5-HT1B AND H5-HT1D RECEPTORS

Despite only modest homology between h5-HT1B and h5-HT1D receptor amin o acid sequences, these receptors display a remarkably similar pharmac ology. To date there are few compounds which discriminate be tween the se receptor subtypes and those with some degree of selectivity, such a s ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ]-2' -methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1, 1'-biphenyl)-4-carboxam ide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl- 2-propanol), which display high affinity and selectivity for h5-HT1B a nd h5-HT1D receptors, respectively. In receptor binding studies on hum an receptors expressed in CHO cells, SB-216641 has high affinity (pK(i ) = 9.0) for h5-HT1D receptors and has 25-fold lower affinity at h5-HT 1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h 5-HT1D (pK(i) = 7.9) than 5-HT1B receptors. Similar affinities for the se compounds were determined on native tissue 5-HT1B receptors in guin ea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [S-35]GTP gamma S binding assay and in a cAMP accumulat ion assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor bind ing affinities. In the cAMP accumulation assay, results from pK(B) mea surements on the compounds again correlated with receptor binding affi nities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D re ceptor mediated responses.