Premium
The contribution of charge to affinity at functional (M 3 ) muscarinic receptors in guinea‐pig ileum assessed from the effects of the carbon analogue of 4‐DAMP methiodide
Author(s) -
Barlow R.B.,
Bond Susan,
Holdup D.W.,
Howard J.A.K.,
McQueen D.S.,
Paterson Anne,
Veale M.A.
Publication year - 1992
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.1476-5381.1992.tb14418.x
Subject(s) - methiodide , muscarinic acetylcholine receptor , damp , chemistry , stereochemistry , receptor , muscarinic acetylcholine receptor m3 , biochemistry , physics , meteorology
1 4‐Diphenylacetoxy‐1:1‐dimethyl cyclo hexane (carbo‐4‐DAMP) is the carbon analogue of 4‐diphenylacetoxy‐ N ‐methylpiperidine (4‐DAMP) methiodide. The compounds differ only in that the quarternary nitrogen atom in 4‐DAMP methiodide is replaced by a quaternary carbon atom, which is uncharged. 2 Carbo‐4‐DAMP appears to act competitively at functional (M 3 ) muscarinic receptors in guinea‐pig ileum. Estimates of log affinity constant are 6.0 at 30°C and 5.9 at 37°C, i.e. the compound has 0.1% of the affinity of 4‐DAMP methobromide. 3 The absence of charge makes little difference to the conformation as determined by X‐ray crystallography. The bond lengths and angles are very similar, though the bonds in the cyclo hexane ring of carbo‐4‐DAMP are consistently slightly longer than those in the piperidinium ring of 4‐DAMP methiodide, and the presence of the charge slightly reduces the space between molecules. 4 The difference between the affinities of 4‐DAMP methobromide and carbo‐4‐DAMP indicates that the contribution of coulombic forces to the binding between 4‐DAMP methiodide and muscarinic (M 3 ) receptors is at least 17 kJ mol −1 (4.1 kcal mol −1 ) at 37°C. How much this is an underestimate depends upon how much hydrophobic binding is greater with the uncharged compound.