Development of allosteric modulators of GPCRs for treatment of CNS disorders.
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.
Division of Neuropathology, Department of Pathology, Microbiology and Immunology, Vanderbilt University, USA.
Hilary Highfield
HH
Nickols
P Jeffrey
PJ
Conn
D000494:Allosteric Regulation / Q000187:drug effects; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D055808:Drug Discovery; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*
D043562:Receptors, G-Protein-Coupled
(+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one; (1-(4-cyano-4-(pyridine-2-yl)piperidine-1-yl)methyl-4-oxo-4H-quinolizine-3-carboxylic acid); (1S,2S)-N(1)-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide; (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid; (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl)(cis-4-methoxycyclohexyl) methanone; (3aS,5S,7aR)-methyl 5-hydroxy-5-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate; 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine; 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1Himidazol-4-yl)ethynyl)pyridine; 2-methyl-6-(2-phenylethenyl)pyridine; 2-methyl-6-(phenylethynyl)-pyridine; 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one; 3[(2-methyl-1,3-thiazol-4-yl)ethylnyl]pyridine; 4-((E)-styryl)-pyrimidin-2-ylamine; 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide; 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine; 5-methyl-6-(phenylethynyl)-pyridine; 5MPEP; 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; 6-OHDA; 6-hydroxydopamine; 6-methyl-2-(phenylazo)-3-pyridinol; 77-LH-28-1; 7TMR; AC-42; ACPT-1; AChE; AD; ADX71743; AFQ056; APP; Allosteric modulator; Alzheimer's disease; BINA; BQCA; CDPPB; CFMMC; CNS; CPPHA; CTEP; DA; DFB; DHPG; Drug discovery; ERK1/2; FMRP; FTIDC; FXS; Fragile X syndrome; GABA; GPCR; JNJ16259685; L-AP4; L-DOPA; Lu AF21934; Lu AF32615; M-5MPEP; MMPIP; MPEP; MPTP; MTEP; Metabotropic glutamate receptor; Muscarinic acetylcholine receptor; N-[4-chloro-2[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl]-2-hydrobenzamide; N-methyl-d-aspartate; N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide; NAM; NMDA; PAM; PCP; PD; PD-LID; PET; PHCCC; PQCA; Parkinson's disease; Parkinson's disease levodopa-induced dyskinesia; SAM; SIB-1757; SIB-1893; TBPB; [(3-fluorophenyl)methylene]hydrazone-3-fluorobenzaldehyde; acetylcholinesterase; amyloid precursor protein; benzylquinolone carboxylic acid; central nervous system; dihydroxyphenylglycine; dopamine; extracellular signal-regulated kinase 1/2; fragile X mental retardation protein; l-(+)-2-amino-4-phosphonobutyric acid; l-3,4-dihydroxyphenylalanine; mGlu; metabotropic glutamate receptor; negative allosteric modulator; phencyclidine; positive allosteric modulator; positron emission tomography; potassium 30-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5yl)oxy]methyl)biphenyl l-4-carboxylate; seven transmembrane receptor; silent allosteric modulator; γ-aminobutyric acid