Creation of a constitutively activated state of the 5-HT2A receptor by site-directed mutagenesis: revelation of inverse agonist activity of antagonists.

Abstract:

: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-HT2A receptor, in particular, antipsychotic drugs, exhibit inverse agonist activity at the constitutively active 5-HT2A receptor. All of the drugs tested reduced basal IP production of constitutively active 5-HT2A 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-HT2A receptor may be a key component of their mechanism of action.

journal_name

Ann N Y Acad Sci

authors

Egan C,Herrick-Davis K,Teitler M

doi

10.1111/j.1749-6632.1998.tb10184.x

subject

Has Abstract

pub_date

1998-12-15 00:00:00

pages

136-9

eissn

0077-8923

issn

1749-6632

journal_volume

861

pub_type

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