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Creation of a Constitutively Activated State of the 5‐HT 2A Receptor by Site‐directed Mutagenesis: Revelation of Inverse Agonist Activity of Antagonists
Author(s) -
EGAN C.,
HERRICKDAVIS K.,
TEITLER M.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb10184.x
Subject(s) - inverse agonist , agonist , chemistry , mutagenesis , partial agonist , site directed mutagenesis , receptor , intrinsic activity , revelation , binding site , pharmacology , stereochemistry , biochemistry , mutation , gene , biology , art , literature , mutant
Constitutively active GPCR have revealed novel properties of drugs that exhibit classical competitive antagonism at the native forms of GPCR. These drugs reverse basal levels of constitutive activity, indicating that they have inverse agonist activity. We were interested in determining if competitive antagonists of the native 5‐HT 2A receptor, in particular, antipsychotic drugs, exhibit inverse agonist activity at the constitutively active 5‐HT 2A receptor. All of the drugs tested reduced basal IP production of constitutively active 5‐HT 2A receptors, indicating that they all exhibited inverse agonist activity. Risperidone and ketanserin produced the greatest inhibition of basal IP production resulting in a reduction of basal activity in the C322K mutant receptor of 82% and 80%, respectively. Antipsychotic drugs display inverse agonist activity, indicating that stabilization of the inactive conformation of the 5‐HT 2A receptor may be a key component of their mechanism of action.