title: The contribution of charge to affinity at functional (M3) muscarinic receptors in guinea-pig ileum assessed from the effects of the carbon analogue of 4-DAMP methiodide.
abstract: 1. 4-Diphenylacetoxy-1:1-dimethyl cyclohexane (carbo-4-DAMP) is the carbon analogue of 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methiodide. The compounds differ only in that the quaternary 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 (M3) muscarinic receptors in guinea-pig ileum. Estimates of log affinity constant are 6.0 at 30 degrees C and 5.9 at 37 degrees 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 cyclohexane 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 (M3) receptors is at least 17 kJ mol-1 (4.1 kcal mol-1) at 37 degrees C. How much this is an underestimate depends upon how much hydrophobic binding is greater with the uncharged compound.
authors.affiliation: Department of Pharmacology, Bristol University.
authors.forename: R B
authors.initials: RB
authors.lastname: Barlow
authors.forename: S
authors.initials: S
authors.lastname: Bond
authors.forename: D W
authors.initials: DW
authors.lastname: Holdup
authors.forename: J A
authors.initials: JA
authors.lastname: Howard
authors.forename: D S
authors.initials: DS
authors.lastname: McQueen
authors.forename: A
authors.initials: A
authors.lastname: Paterson
authors.forename: M A
authors.initials: MA
authors.lastname: Veale
mesh_terms: D000818:Animals; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D066298:In Vitro Techniques; D010880:Piperidines; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D003510:Cyclohexanes; D010880:Piperidines; D011976:Receptors, Muscarinic; C077361:4-diphenylacetoxy-1,1-dimethylcyclohexane; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium