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Constitutive activity of the histamine H1 receptor reveals inverse agonism of histamine H1 receptor antagonists

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Abstract

Transient expression of the wild-type human histamine H1 receptor in SV40-immortalised African green monkey kidney cells resulted in an agonist-independent elevation of the basal levels of the second messenger inositoltrisphospate. Several histamine H1 receptor antagonists, including the therapeutically used anti-allergics cetirizine, loratadine and epinastine reduced this constitutive histamine H1 receptor activity. Inverse agonism, i.e., stabilisation of an inactive conformation of the human histamine H1 receptor, may therefore be a key component of the anti-allergic mechanism of action of clinically used antihistamines.

Introduction

The recent notion of constitutive signalling of G-protein-coupled receptors has fundamentally changed insights in receptor pharmacology and led to a reclassification of antagonists into inverse agonists, agents which display negative intrinsic activitity, and neutral antagonists, which do not affect receptor activity Milligan et al., 1995, Leurs et al., 1998. The actual therapeutic importance of constitutive G-protein-coupled receptor activity has not been clarified yet; however, for a proper evaluation of drug action this new aspect in receptor pharmacology should not be ignored. In view of the widespread therapeutic use of histamine H1 receptor antagonists in allergy (Woosley, 1996), we investigated the constitutive histamine H1 receptor activity and inverse agonistic activity of several histamine H1 receptor antagonists.

Section snippets

Experimental

To determine whether wild-type human histamine H1 receptors exhibit constitutive activity, we transiently transfected (2.5 μg DNA/1×106 cells) SV40-immortalised African green monkey kidney (COS-7) cells with either pcDEF3 or pcDEF3 containing the gene for the wild-type human histamine H1 receptor (pcDEF3hH1), using the DEAE–dextran method (Wieland et al., 1999). Transient expression resulted in a high affinity binding site for the histamine H1 receptor antagonist [3H]mepyramine (pKD=8.8±0.1, n

Discussion

In this study, we show for the first time constitutive activity of the wild-type human histamine H1 receptor. Histamine H1 receptor antagonists are widely used to relieve the symptoms of allergic reactions and have become one of most prescribed drug families in Western countries (Woosley, 1996). We have identified well-known therapeutics as cetirizine (Zyrtec®), epinastine (Flurinol®), loratadine (Claritin®) as inverse agonists, which sheds new light on their presumed mechanism of action. At

Acknowledgements

The research of the authors is supported in part by UCB Pharma (Belgium) and the EU BIOMED 2 programme ‘Inverse Agonism. Implications for Drug Research’. Gifts of acrivastine (The Wellcome Foundation, United Kingdom), (R)- and (S)-cetirizine hydrochloride (UCB Pharma, Belgium), epinastine hydrochloride (Boehringer Mannheim, Germany), loratadine hydrochloride (Schering Plough, USA), and pcDEF3 (Dr. J.A. Langer, USA) are greatly acknowledged.

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