Tag: Functional

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Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.

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Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.

J Med Chem. 2015 May 20;

Authors: Tichenor MS, Thurmond RL, Venable JD, Savall BM

Abstract
Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This perspective provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

PMID: 25993395 [PubMed – as supplied by publisher]

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Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Adv Exp Med Biol. 2011;704:731-47

Authors: Wang YX, Zheng YM

Multiple canonical or classic transient receptor potential (TRPC) molecules are expressed in animal and human airway smooth muscle cells (SMCs). TRPC3, but not TRPC1, is a major molecular component of native non-selective cation channels (NSCCs) to contribute to the resting [Ca(2+)](i) and muscarinic increase in [Ca(2+)](i) in freshly isolated airway SMCs. TRPC3-encoded NSCCs are significantly increased in expression and activity in airway SMCs from ovalbumin-sensitized/challenged “asthmatic” mice, whereas TRPC1-encoded channel activity, but not its expression, is largely augmented. The upregulated TRPC3- and TRPC1-encoded NSCC activity both mediate “asthmatic” membrane depolarization in airway SMCs. Supportively, tumor necrosis factor-? (TNF?), an important asthma mediator, increases TRPC3 expression, and TRPC3 gene silencing inhibits TNF?-mediated augmentation of acetylcholine-evoked increase in [Ca(2+)](i) in passaged airway SMCs. In contrast, TRPC6 gene silencing has no effect on 1-oleoyl-2-acetyl-sn-glycerol (OAG)-evoked increase in [Ca(2+)](i) in primary isolated cells. These findings provide compelling information indicating that TRPC3-encoded NSCCs are important for physiological and pathological cellular responses in airway SMCs. However, continual studies are necessary to further determine whether, which, and how TRPC-encoded channels are involved in cellular responses in normal and diseased (e.g., asthmatic) airway SMCs.

PMID: 21290324 [PubMed – in process]

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