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Modulation of the structure‐binding relationships of antagonists for muscarinic acetylcholine receptor subtypes
Author(s) -
Pedder E. Kristina,
Eveleigh Phike,
Poyner David,
Hulme Edward C.,
Birdsall Nigel J.M.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb09827.x
Subject(s) - muscarinic acetylcholine receptor , pirenzepine , receptor , chemistry , allosteric regulation , muscarinic acetylcholine receptor m2 , biophysics , antagonist , muscarinic acetylcholine receptor m1 , affinities , competitive antagonist , muscarinic acetylcholine receptor m3 , acetylcholine receptor , acetylcholine , pharmacology , stereochemistry , biochemistry , biology
1 Membranes from rat cerebral cortex, myocardium and extraorbital lacrimal gland were used as sources of M 1 M 2 and M 3 muscarinic acetylcholine receptors respectively and the affinities of seven antagonists for the three subtypes were examined under different experimental conditions. 2 The affinities for the membrane‐bound receptors were measured at different ionic strengths and temperatures and compared with those determined on the receptor solubilised in the neutral detergent digitonin or the zwitterionic detergent, CHAPSO. 3 The range of measured affinity constants of a given antagonist for a specific subtype varied from 2 (atropine at M 1 receptors) to 1000 (AF‐DX 116 at M 2 receptors). 4 As a consequence of these changes in affinity, which were dependent on the drug, the subtype and the experimental conditions, both the structure‐binding relationships of a given subtype can be markedly changed as well as the selectivity of a drug for the different subtypes. For example it is possible to change the relative affinities of AF‐DX 116 and gallamine at membrane‐bound M 1 receptors from 50:1 to 1:60. 5 Experimental conditions for the observation of high selectivity of pirenzepine, AF‐DX 116, gallamine and hexahydrosiladiphenidol for the three subtypes are given. 6 When the receptors are removed from their membrane environment by solubilisation in detergent, antagonist affinities are changed but the subtypes still retain different structure‐binding relationships. 7 In general, AF‐DX 116 and the allosteric antagonist, gallamine, behave differently from the other antagonists, suggesting that they bind in different ways to muscarinic receptors. 8 Careful attention should therefore be paid to the experimental conditions in binding assays used to assess the affinities and selectivities of new muscarinic antagonists in order to avoid misleading results. 9 The ability to produce enhanced or attenuated affinities and selectivities of antagonists, resulting from the induction of different conformations of the receptor by a variety of physical, chemical or molecular biological perturbations may lead to a better understanding of the structural basis of drug receptor interactions.