Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABAA receptors

doi:10.1016/S0960-894X(01)00184-6

Bioorganic & Medicinal Chemistry Letters

Volume 11, Issue 12, 18 June 2001, Pages 1573-1577

https://doi.org/10.1016/S0960-894X(01)00184-6 Get rights and content

Abstract

The potency and efficacy of a series of bioisosterically modified GABA analogues were determined electrophysiologically using heteromeric GABA_A receptors expressed in Xenopus oocytes. These agonist parameters were shown to be strongly dependent on the receptor subunit combination. On the other hand, the antagonist potencies of the classical GABA_A antagonists SR 95531 (7) and BMC (8) and also of 5g and the phosphinic acid bioisosteres of 5a, compounds 5f and 6, were essentially independent of the receptor subunit combinations.

The structure of the carboxyl bioisosteric groups is of major pharmacological importance. Whereas 5a is a GABA_A agonist, 5b and 5d are generally low-efficacy partial agonists, and 5f is an antagonist.

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Acknowledgements

This work was supported by the Lundbeck Foundation and the Danish Medicinal Research Council. The secretarial assistance of Anne Nordly is gratefully acknowledged.

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^†: Present address: Departments of Pharmacology and Medicinal Chemistry, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby-Copenhagen, Denmark.

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Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABAA receptors

Abstract

Section snippets

Acknowledgements

Trends Pharmacol. Sci.

Eur. J. Pharm. Sci.

Adv. Drug Res.

Toxicol. Lett.

Eur. J. Pharmacol.

J. Med. Chem.

Pharmacol. Rev.

Proc. Natl. Acad. Sci. U.S.A.

Mol. Pharmacol.

Org. Lett.

Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA_A receptors