Development of allosteric modulators of GPCRs for treatment of CNS disorders

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.

Keywords: (+)-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.

Figure 1

Basal ganglia circuit. The basal ganglia are a collection of interconnected deep gray subcortical nuclei that are essential in the control of motor function. The major input nucleus of the basal ganglia is the striatum (caudate and putamen). The cerebral cortex sends stimulatory inputs to the striatum, including primary motor cortex. The major output nuclei include the substantia nigra pars reticulata (SNr) and the internal globus pallidus (GPi). Two major parallel pathways project from the striatum to the major output nuclei of the basal ganglia. The direct pathway contains inhibitory projections from the striatum to the output nuclei. GABAergic neurons in the striatum that express D₁ dopamine receptors project to the SNr and GPi. The indirect pathway is polysynaptic, and ends in excitatory projections to the output nuclei from the subthalamic nucleus (STN). GABAergic neurons in the striatum that express D₂ dopamine receptors project to the external globus pallidus (GPe), and subsequently the GPe sends inhibitory projections to the STN. The result of disruption of the indirect pathway is disinhibition of the STN, and net increased excitatory stimulation to the output nuclei. The balanced activity between the direct pathway inhibition of the output nuclei and the indirect pathway excitation is essential for the normal control of motor activity. The action of dopamine in the striatum decreases transmission through the indirect pathway and increases transmission through the direct pathway. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) in PD leads to decreased inhibitory tone in the direct pathway with subsequent increased stimulatory tone in the indirect pathway, increased GABAergic tone at the thalamus and reduced excitation of the motor cortex. Metabotropic glutamate receptors are expressed throughout the basal ganglia. The Group I receptors (mGlu₁ and mGlu₅) are expressed in multiple locations in the basal ganglia. They are located post-synaptically, and inhibit the basal ganglia response to dopamine. Group II receptors (mGlu_2/3) are located presynaptically to the cortico-striatal, STN-SNr, and STN-SNc synapses. Of the Group III receptors, mGlu₄ is known to modulate corticostriatal, STN-SNr, as well as intrastriatal GABAergic synapses. Cholinergic systems modulate basal ganglia function. Of primary importance, tonically active cholinergic interneurons in the striatum release acetylcholine to modulate basal ganglia and motor function. They act project to neighboring medium spiny neurons in the striatum. Muscarinic acetylcholine receptors are expressed in the basal ganglia. M₁, M₂, M₄ receptors are expressed in the striatum, with M₅ receptors expressed on dopaminergic neurons in the ventral tegmental area (VTA) and SNc. M₄ receptors colocalize with D₁ expressing neurons in the striatum. The development of subtype specific allosteric modulators of muscarinic ACh receptors will allow for further characterization of their location and function in the basal ganglia circuit. Adapted from Dickerson and Conn 2012, Johnson et al. 2009, Conn et al. 2005, and Wichmann and DeLong, 1996.