Analysis of the behaviour of selected CCKB/gastrin receptor antagonists inradioligand binding assays performed in mouse and rat cerebral cortex

1. The previously described complex behaviour of the CCKB/gastrin receptor antagonist, L-365,260, in radioligand binding assays could be explained by a variable population of two binding sites. We have investigated whether ot her CCKB/gastrin receptor ligands PD134,308, PD140,376, YM022 and JB931S2) can distinguish between these sites. 2 In the mouse cortex assay; Hill slopes were not different from unity and the ligand pK(1) values did not differ when either [I-125]-BH-CCK-8S or [H- 3]-PD140,376 was used as label as expected for a single site (G(2)). 3 In the rat cortex, where previous:analysis of replicate (n = 48) L-365,26 0 data indicated the presence of two CCK(B/)gastrin sites (G(1) and G(2)), the competition data for PD134,308, PD140,376, YM022 and JB93182 could be e xplained by a homogeneous population of CCK(B/)gastrin sites because the Hi llslope estimates were not significantly different from unity. However, the estimated affinity values for JB93182 and YM022 were significantly higher and that;for PD134,308 was significantly lower than those obtained in the m ouse cortex when the same radioligand was used. In view of our previous dat a obtained with L-365,260, the rat cortex data were also interpreted using a two-site model. In this analysis, SR27897 expressed similar to 9 fold, PD 134,308 similar to 13 fold and PD140,376 similar to 11 fold selectivity for the G2 site. In contrast, JB93182 expressed similar to 23 fold and YM022 s imilar to 4 fold selectivity for the G(1) site. If the two-site interpretat ion of the data is valid then, because of its reverse selectivity to L-365, 260, JB93182 has been identified as a compound which if radiolabelled could provide a test of this receptor subdivision.