Chemical Optimization of Advanced mGlu4 Lead Candidates
The primary pathophysiological change giving rise to the symptoms of Parkinson's disease (PD) is a loss of the dopaminergic neurons in the substantia nigra pars compacta (SNc) that are involved in modulating the function of basal ganglia (BG) nuclei. Unfortunately, traditional therapies for treatment of PD based on dopamine replacement strategies eventually fail in most patients and are more ..
The primary pathophysiological change giving rise to the symptoms of Parkinson's disease (PD) is a loss of the dopaminergic neurons in the substantia nigra pars compacta (SNc) that are involved in modulating the function of basal ganglia (BG) nuclei. Unfortunately, traditional therapies for treatment of PD based on dopamine replacement strategies eventually fail in most patients and are associated with numerous side effects. A great deal of effort has been focused on developing a detailed understanding of the circuitry and function of the BG to develop novel, nondopaminergic, approaches for restoring normal BG function in PD patients. Exciting advances suggest that metabotropic glutamate receptors (mGlus), including the group III mGlus (mGlu4, -7 and -8), play important roles in regulating transmission through the BG and could serve as targets for novel PD therapeutics (3). For instance, mGlu4 activation reduces overactive GABA release at a specific inhibitory BG synapse (12,19,9) and reverses motor deficits in a variety of rodent PD models (12,19,10,8,16).
To more selectively activate mGlu4 and improve upon the pharmacokinetic liabilities of glutamate analogs, we and others have developed novel positive allosteric modulators (PAMs) which potentiate glutamate function at mGlu4 (11,12,14,15,4,21,7,6); several of these tool compounds exhibit antiparkinsonian and neuroprotective effects in multiple rodent PD models (12,1,14,7,6). Unfortunately, many available compounds have lacked the necessary pharmacokinetic properties required for study of mGlu4 function via systemic routes of administration. Future compounds developed should exhibit sufficient potency, efficacy, and pharmacokinetic properties, including brain penetration, to make useful probes to progress mGlu4 biology, which will undoubtedly allow the intense study of mGlu4 activation in multiple areas of neuroscience such as psychiatric disorders (18,17), cancer (5), and addiction (2).
Potency and efficacy of compounds will be determined by performing concentration-response curves (CRCs, 10 points, ranging from approximately 30 microM-1 nM at 0.3% final DMSO concentration) at human mGlu4 using a calcium assay in which the cells express the chimeric G protein Gqi5 to couple mGlu4 to calcium mobilization (13,14,7,6). PAMs with EC50 values less than 500 nM versus human mGlu4 will next be evaluated for potency versus rat mGlu4 in a thallium flux assay measuring coupling of rat mGlu4 to G Protein-coupled Inwardly Rectifying Potassium (GIRK) Channels (13,6). Following potency evaluation at human and rat mGlu4, PAMs with EC50 values less than 500 nM at rat mGlu4 will be evaluated for their ability to left-shift the CRC of glutamate for rat mGlu4 in a thallium flux assay (13,14,7,6). PAMs with a fold-shift of the glutamate CRC of > 5 will then be evaluated for Tier 1 DMPK assays including plasma protein binding (PPB), intrinsic clearance, and inhibition of cytochrome p450 enzymes (CYP) (4,6). Next, compounds demonstrating PPB > 1% free and moderate clearance will be evaluated for CNS exposure and Plasma:Brain levels using an in vivo snapshot PK paradigm and will be examined for their selectivity for mGlu4 relative to other mGlu subtypes evaluated (4,6). Novel mGlu4 PAMs showing a CNS exposure > PAM EC50, a Brain:Plasma ratio of >0.5, and at least a 50-fold or greater selectivity versus other mGlu subtypes will next be evaluated in a preclinical model of PD: haloperidol-induced catalepsy (HIC) (20). mGlu4 PAMs demonstrating activity in HIC at a dose of < 30 mg/kg will have their ancillary pharmacology fully evaluated and those compounds that show no significant off-target activity, CaCo permeability > 10 cm/s-6, and suitable solubility will be declared an MLPCN probe. The ultimate goal of this project from the PI's perspective is to generate compounds which should exhibit sufficient potency, efficacy, and pharmacokinetic properties, including brain penetration, to make useful probes to progress mGlu4 biology.
1. Battaglia, G., C. L. Busceti, et al. (2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine." J Neurosci 26(27): 7222-9.
2. Blednov, Y. A., D. Walker, et al. (2004). "Mice lacking metabotropic glutamate receptor 4 do not show the motor stimulatory effect of ethanol." Alcohol 34(2-3): 251-9.
3. Conn, P. J., G. Battaglia, et al. (2005). "Metabotropic glutamate receptors in the basal ganglia motor circuit." Nat Rev Neurosci 6(10): 787-98.
4. Engers, D. W., C. M. Niswender, et al. (2009). "Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)." J Med Chem 52(14): 4115-8.
5. Iacovelli, L., A. Arcella, et al. (2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas." J Neurosci 26(32): 8388-97.
6. Jones, C. K., M. Bubser, et al. (2012). "The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease." J Pharmacol Exp Ther 340(2): 404-21.
7. Jones, C. K., D. W. Engers, et al. (2011). "Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model." J Med Chem 54(21): 7639-47.
8. Konieczny, J., J. Wardas, et al. (2007). "The influence of group III metabotropic glutamate receptor stimulation by (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mRNA expression in rats." Neuroscience 145(2): 611-20.
9. Macinnes, N. and S. Duty (2008). "Group III metabotropic glutamate receptors act as hetero-receptors modulating evoked GABA release in the globus pallidus in vivo." Eur J Pharmacol 580(1-2): 95-9.
10. MacInnes, N., M. J. Messenger, et al. (2004). "Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat." Br J Pharmacol 141(1): 15-22.
11. Maj, M., V. Bruno, et al. (2003). "(-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection." Neuropharmacology 45(7): 895-906.
12. Marino, M., O. Valenti, et al. (2003). "Glutamate receptors and Parkinson's disease : opportunities for intervention." Drugs Aging 20(5): 377-97.
13. Niswender, C. M., K. A. Johnson, et al. (2008a). "A novel assay of Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors." Mol Pharmacol 73(4): 1213-24.
14. Niswender, C. M., K. A. Johnson, et al. (2008b). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4." Mol Pharmacol 74(5): 1345-58.
15. Niswender, C. M., E. P. Lebois, et al. (2008c). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators." Bioorg Med Chem Lett 18(20): 5626-30.
16. Ossowska, K., J. Konieczny, et al. (2007). "An influence of ligands of metabotropic glutamate receptor subtypes on parkinsonian-like symptoms and the striatopallidal pathway in rats." Amino Acids 32(2): 179-88.
17. Stachowicz, K., E. Chojnacka-Wojcik, et al. (2006). "Anxiolytic-like effects of group III mGlu receptor ligands in the hippocampus involve GABAA signaling." Pharmacol Rep 58(6): 820-6.
18. Stachowicz, K., K. Klak, et al. (2004). "Anxiolytic-like effects of PHCCC, an allosteric modulator of mGlu4 receptors, in rats." Eur J Pharmacol 498(1-3): 153-6.
19. Valenti, O., M. J. Marino, et al. (2003). "Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse." J Neurosci 23(18): 7218-26.
20. Varty, G. B., R. A. Hodgson, et al. (2008). "The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates." Psychopharmacology (Berl) 200(3): 393-401.
21. Williams, R., C. M. Niswender, et al. (2009). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead." Bioorg Med Chem Lett 19(3): 962-6.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML292
PubChem Substance ID (SID) for probe 1: 134213607
PubChem Compound ID (CID) for probe 1: 56587900
Probe type for probe 1: PAM
IC50/EC50 (nM) for probe 1: <1200
Target for probe 1: rmGlu4; hmGlu4 (gi: 120659920)
Disease relevance for probe 1: Stroke
Anti-target for probe 1: mGlu1; mGlu2; mGlu3; mGlu5; mGlu6; mGlu7; mGlu8; PanLabs(Ricerca); Millipore
Fold selectivity for probe 1: >20
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133426/ (ID: 3026150)
Grant number for probe 1: NS053536-01
PubMed Publication ID (PMID) for probe 1: 22088953
NCBI Book chapter title for probe 1: Discovery of a novel metabotropic glutamate receptor 4 (mGlu4) positive allosteric modulator (PAM) extended probe: Characterization of ML292, a potent and selective mGlu4 PAM which produces efficacy alone or in combination with L-DOPA in preclinical rodent models of Parkinson's disease