In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists

Abstract

The human histamine H 1 receptor (H 1 R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H 1 R by evaluating Ͼ130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H 1 R agonist (Mol Pharmacol 65: 538 -549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H 1 R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…This is also in keeping with the well known sedative action of the H 1 receptor antagonists (Bovet, 1950), which function as inverse agonists, stabilizing the receptor in its inactive state (R) (Lin et al, 1996;Bakker et al, 2002Bakker et al, , 2007. Many antidepressant and antipsychotic drugs also bind to the H 1 receptor (Richelson, 1978;Kim et al, 2007).…”

Constitutively Active Mutants of the Histamine H1 Receptor Suggest a Conserved Hydrophobic Asparagine-Cage That Constrains the Activation of Class A G Protein-Coupled Receptors

“…Because we aimed at the generation and characterization of a large number of mutant receptors, we selected R-SAT functional assays for the initial characterization because the R-SAT assay is extremely robust, allows high throughput, and yields a similar H 1 R pharmacological profile for a wide variety of inverse H 1 R agonists compared with the more standard NF-B reportergene assay (see Bakker et al, 2007). …”

Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

“…2). (14), which is higher than that of mepyramine at 2.0 nM (12), carebastine should have stronger inverse agonistic activity than mepyramine. Next, we investigated the effect of these antihistamines on H1R gene expression in HeLa cells.…”