SAR Studies on Carboxylic Acid Series M₁ Selective Positive Allosteric Modulators (PAMs)

Title:SAR Studies on Carboxylic Acid Series M₁ Selective Positive Allosteric Modulators (PAMs)

Volume: 14 Issue: 15

Author(s): Scott D. Kuduk and Douglas C. Beshore

Affiliation:

Keywords: Allosteric, Alzheimer's, BQCA, modulator, muscarinic, positive, quinolone.

Abstract: There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M₁ muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M₁ muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M₂ to M₅ sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M₁ is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M₁ receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M₁ PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.

Cite this article as:

Kuduk D. Scott and Beshore C. Douglas, SAR Studies on Carboxylic Acid Series M₁ Selective Positive Allosteric Modulators (PAMs), Current Topics in Medicinal Chemistry 2014; 14 (15) . https://dx.doi.org/10.2174/1568026614666140826120224