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Thermodynamic analysis of ligands at cholecystokinin CCK(2) receptors in rat cerebral cortex.

Harper EA, Roberts SP, Kalindjian SB

1James Black Foundation, Dulwich, London, UK.

Background and purpose:Several studies using radioligand binding assays, have shown that measurement of thermodynamic parameters can allow discrimination of agonists and antagonists (Weiland et al., 1979; Borea et al., 1996a). Here we investigate whether agonists and antagonists can be thermodynamically discriminated at CCK(2) receptors in rat cerebral cortex.Experimental approach:The pK(L) of [(3)H]-JB93182 in rat cerebral cortex membranes was determined at 4, 12, 21 and 37 degrees C in 50 mM Tris-HCl buffer (buffer B pH 6.96; containing 0.089 mM bacitracin). pK(I) values of ligands of diverse chemical structure and with differing intrinsic activity (alpha), as defined by the lumen-perfused rat and mouse stomach bioassays, were determined in buffer B at 4, 12, 21 and 37 degrees C.Key results:[(3)H]-JB93182 labelled a homogeneous population of receptors in rat cerebral cortex at 4, 12, 21 and 37 degrees C and the pK(L) and B(max) were not altered by incubation temperature. [(3)H]-JB93182 binding reached equilibrium after 10, 50, 90 and 220 min at 37, 21, 12 and 4 degrees C, respectively. pK(I) values for R-L-365,260, R-L-740,093, YM220, PD134,308 and JB95008 were higher at 4 degrees C than at 37 degrees C. There was no effect of temperature on pK(I) values for pentagastrin, CCK-8S, S-L-365,260, YM022, PD140,376 and JB93242.Conclusions and implications:CCK(2) receptor agonists and antagonists at rat CCK(2) receptors cannot be discriminated by thermodynamic analysis using [(3)H]-JB93182 as the radioligand.British Journal of Pharmacology (2007) 151, 1352-1367; doi:10.1038/sj.bjp.0707355; published online 25 June 2007.

Published 16 August 2007 in Br J Pharmacol, 151(8): 1352-67.
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