TY - JOUR
T1 - Functional partial agonism at cloned human muscarinic acetylcholine receptors
AU - Bräuner-Osborne, Hans
AU - Ebert, B
AU - Brann, M R
AU - Falch, E
AU - Krogsgaard-Larsen, P
PY - 1996/10/10
Y1 - 1996/10/10
N2 - We have previously defined the concept of functional partial agonism as the partial agonist responses recorded in brain slices after administration of full ionotropic glutamate receptor agonists and competitive antagonists at fixed ratios. Functional partial agonism can be established at any level of maximal response, depending on the molar ratio of agonist and antagonist used. Using recombinant human muscarinic acetylcholine receptors (m1 and m5) and the functional assay, receptor selection and amplification technology (R-SAT), we have now shown that co-administration of the full agonist, carbachol, and a competitive antagonist, atropine or pirenzepine, at fixed ratios display functional partial agonism. The levels of apparent intrinsic activity of the functional partial agonist responses were shown to be dependent of the receptor density and G-protein concentration in the same manner as that determined for the true partial muscarinic agonist, 4-[N-(3-chlorophenyl)carbamoyloxy]-2-butynyltrimethylammonium chloride (McN A-343). Thus, functional as well as true partial agonist responses became more efficacious and potent with increasing receptor and G-protein levels. The level of maximal functional partial agonist response, which is dependent on the agonist/antagonist ratio, is predictable from the Waud equation, describing competitive receptor/ligand interactions. In agreement with the relative antagonist potencies of pirenzepine at m1 and m5, a 10:1 ratio of carbachol and pirenzepine produced very low-efficacy functional partial agonism, approaching full antagonism, at m1 but virtually full agonism at the m5 subtype.
AB - We have previously defined the concept of functional partial agonism as the partial agonist responses recorded in brain slices after administration of full ionotropic glutamate receptor agonists and competitive antagonists at fixed ratios. Functional partial agonism can be established at any level of maximal response, depending on the molar ratio of agonist and antagonist used. Using recombinant human muscarinic acetylcholine receptors (m1 and m5) and the functional assay, receptor selection and amplification technology (R-SAT), we have now shown that co-administration of the full agonist, carbachol, and a competitive antagonist, atropine or pirenzepine, at fixed ratios display functional partial agonism. The levels of apparent intrinsic activity of the functional partial agonist responses were shown to be dependent of the receptor density and G-protein concentration in the same manner as that determined for the true partial muscarinic agonist, 4-[N-(3-chlorophenyl)carbamoyloxy]-2-butynyltrimethylammonium chloride (McN A-343). Thus, functional as well as true partial agonist responses became more efficacious and potent with increasing receptor and G-protein levels. The level of maximal functional partial agonist response, which is dependent on the agonist/antagonist ratio, is predictable from the Waud equation, describing competitive receptor/ligand interactions. In agreement with the relative antagonist potencies of pirenzepine at m1 and m5, a 10:1 ratio of carbachol and pirenzepine produced very low-efficacy functional partial agonism, approaching full antagonism, at m1 but virtually full agonism at the m5 subtype.
KW - (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
KW - Atropine
KW - Binding, Competitive
KW - Carbachol
KW - Cells, Cultured
KW - Cloning, Molecular
KW - Dose-Response Relationship, Drug
KW - GTP-Binding Proteins
KW - Humans
KW - Muscarinic Agonists
KW - Muscarinic Antagonists
KW - Nicotinic Agonists
KW - Pirenzepine
KW - Receptors, Muscarinic
M3 - Journal article
C2 - 8905341
SN - 0014-2999
VL - 313
SP - 145
EP - 150
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -