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Development of Allosteric Modulators of GPCRs for Treatment of CNS Disorders

Development of Allosteric Modulators of GPCRs for Treatment of CNS Disorders

Hilary Highfield Nickols, P Jeffrey Conn

Neurobiol Dis. 2014 Jan;61:55-71.

PMID: 24076101

Abstract:

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.

Chemicals Related in the Paper:

Catalog Number	Product Name	CAS Number	Price
AP1431641290	ADX71743	1431641-29-0	Price
AP693288970	CPPHA	693288-97-0	Price
AP7370210	SIB 1893	7370-21-0	Price

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