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Structural Studies on D 2 Dopamine Receptors: Mutation of a Histidine Residue Specifically Affects the Binding of a Subgroup of Substituted Benzamide Drugs
Author(s) -
Woodward Robert,
Daniell Sarah J.,
Strange Philip G.,
Naylor Louise H.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62051664.x
Subject(s) - sulpiride , benzamide , receptor , tiapride , chemistry , histidine , mutant , competitive antagonist , biochemistry , dopamine receptor d2 , stereochemistry , antagonist , pharmacology , biology , amino acid , gene
A histidine residue (His 394 ) that is likely to be located in the ligand‐binding region of the D 2 dopamine receptor has been mutated to a leucine (Leu 394 ), and the properties of the mutant receptor have been determined. For a range of antagonists the mutation has only a minor effect on the affinity of the receptor for the antagonist. The mutation does, however, elicit a structurally specific effect on the affinity with which certain members of the substituted benzamide class of antagonist bind to the receptor. Some of these drugs, e.g., sulpiride, sultopride, and tiapride, bind with reduced affinity to the mutated receptor, whereas others, e.g., clebopride and metoclopramide, bind with increased affinity. However, the Na + /H + sensitivity of the binding of sulpiride to the receptor is not reduced by the mutation. These findings have been interpreted in terms of the productive or unfavourable interaction of the His 394 residue with these compounds.