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Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of ?7 nicotinic acetylcholine receptors.

ABSTRACT: A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of ?7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human ?7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 ?M. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 ?mol/kg). This effect was blocked by the selective ?7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of ?7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer's disease.

SUBMITTER: Hogenkamp DJ

PROVIDER: S-EPMC3912855 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors.

Hogenkamp Derk J DJ Ford-Hutchinson Thomas A TA Li Wen-Yen WY Whittemore Edward R ER Yoshimura Ryan F RF Tran Minhtam B MB Johnstone Timothy B C TB Bascom Gavin D GD Rollins Hannah H Lu Lena L Gee Kelvin W KW

Journal of medicinal chemistry 20131030 21

A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 μM. Compound 7z was active in reversin ...[more]

PMID: 24098954

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Project description:Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding to an extracellular site located at the interface of two adjacent subunits. In contrast, recent studies have provided evidence that positive allosteric modulators (PAMs) such as TQS (4-(naphthalen-2-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and allosteric agonists such as 4BP-TQS (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) interact at an intrasubunit transmembrane site. Here, we describe the synthesis and pharmacological characterization of a series of chemically related allosteric modulators of the α7 nAChR. Minimal changes in the chemical structure of these compounds have been found to exert profound effects on their pharmacological properties. For example, compounds containing a bromine atom at either the ortho or meta position on the phenyl ring, such as 2BP-TQS (4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and 3BP-TQS (4-(3-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), rather than at the para position (4BP-TQS), display no allosteric agonist activity but retain PAM activity on α7 nAChRs, demonstrating the importance of the location of the halogen atom on pharmacological properties. Replacement of the bromine atom in 4BP-TQS with either a chlorine [4CP-TQS (4-(4-chloroophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] or an iodine atom [4IP-TQS (4-(4-iodoophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] results in compounds that have pharmacological properties characteristic of allosteric agonists but display differences in activation rates, in inactivation rates, and in levels of desensitization. In contrast, replacement of the bromine atom in 4BP-TQS with a fluorine atom [4FP-TQS (4-(4-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] generated a compound that lacks allosteric agonist activity but acts a potentiator of responses to acetylcholine. In addition, 4FP-TQS was found to act as an antagonist of responses evoked by allosteric agonists such as 4BP-TQS. These findings provide evidence of the pharmacological diversity of compounds interacting with the allosteric transmembrane site on α7 nAChRs.

Dataset Information

Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of ?7 nicotinic acetylcholine receptors.

Publications

Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors.

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