FUNCTIONAL PARTIAL AGONISM AT CLONED HUMAN MUSCARINIC ACETYLCHOLINE-RECEPTORS

We have previously defined the concept of functional partial agonism a s the partial agonist responses recorded in brain slices after adminis tration of full ionotropic glutamate receptor agonists and competitive antagonists at fixed ratios. Functional partial agonism can be establ ished at any level of maximal response, depending on the molar ratio o f agonist and antagonist used. Using recombinant human muscarinic acet ylcholine receptors (mi and m5) and the functional assay, receptor sel ection and amplification technology (R-SAT), we have now shown that co -administration of the full agonist, carbachol, and a competitive anta gonist, atropine or pirenzepine, at fixed ratios display functional pa rtial agonism. The levels of apparent intrinsic activity of the functi onal partial agonist responses were shown to be dependent of the recep tor density and G-protein concentration in the same manner as that det ermined for the true partial muscarinic agonist, orophenyl)carbamoylox y]-2-butynyltrimethylammonium chloride (McN A-343). Thus, functional a s well as true partial agonist responses became more efficacious and p otent with increasing receptor and G-protein levels. The level of maxi mal functional partial agonist response, which is dependent on the ago nist/antagonist ratio, is predictable from the Waud equation, describi ng competitive receptor/ligand interactions. In agreement with the rel ative antagonist potencies of pirenzepine at mi and m5, a 10:1 ratio o f carbachol and pirenzepine produced very low-efficacy functional part ial agonism, approaching full antagonism, at mi but virtually full ago nism at the m5 subtype.