ABSTRACT
Restoring the balance between excitatory and inhibitory circuits in the basal ganglia, following the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta, represents a major challenge to treat patients affected by Parkinson's disease (PD). The imbalanced situation in favor of excitation in the disease state may also accelerate excitotoxic processes, thereby representing a potential target for neuroprotective therapies. Reducing the excitatory action of glutamate, the major excitatory neurotransmitter in the basal ganglia, should lead to symptomatic improvement for PD patients and may promote the survival of DA neurons. Recent studies have focused on the modulatory action of metabotropic glutamate (mGlu) receptors on neurodegenerative diseases including PD. Group III mGlu receptors, including subtypes 4, 7 and 8, are largely expressed in the basal ganglia. Recent studies highlight the use of selective mGlu4 receptor positive allosteric modulators (PAMs) for the treatment of PD. Here we review the effects of newly-designed group-III orthosteric agonists on neuroprotection, neurorestoration and reduction of l-DOPA induced dyskinesia in animal models of PD. The combination of orthosteric mGlu4 receptor selective agonists with PAMs may open new avenues for the symptomatic treatment of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Subject(s)
Excitatory Amino Acid Agonists/therapeutic use , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Receptors, Metabotropic Glutamate/agonists , Animals , Basal Ganglia/drug effects , Basal Ganglia/metabolism , Disease Models, Animal , Dyskinesia, Drug-Induced/drug therapy , Excitatory Amino Acid Agonists/pharmacology , Models, Neurological , Neuroprotective Agents/pharmacology , Parkinson Disease/metabolism , Receptors, Metabotropic Glutamate/metabolismABSTRACT
Two glutamic acid analogs (1 SR,3 RS,4 RS)- and (1 SR,3 SR,4 SR)-1-amino-4-phosphono cyclopentane-1,3-dicarboxylic acids (APCPD) have been synthesized. Pure E-(diethoxy-phosphoryl)-acrylic acid ethyl ester was obtained from ethyl propiolate, phenol and triethylphosphite. It was used as dienophile in a Diels-Alder reaction. Oxidation and cyclization afforded 3-(ethoxy-carbonyl)-4-(diethoxy-phosphoryl)-cyclopentanone. Bucherer-Bergs reaction and hydrolysis yielded APCPD-III and -IV which are inactive on mGlu1a receptor and antagonists on mGlu2 and mGlu8a receptors.
Subject(s)
Amino Acids/chemical synthesis , Cyclopentanes/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Amino Acids/chemistry , Amino Acids/pharmacology , Binding Sites/drug effects , Cell Line , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Humans , Hydrogen Bonding , Ligands , Models, Chemical , Models, Molecular , Molecular Structure , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
To investigate the structural requirements for selective activation or blockade of metabotropic glutamate receptors, we developed a pharmacophore model for group I (mGluR1) and group II (mGluR2) agonists. The Apex-3D program was used with a training set of known active, inactive, and/or selective compounds with a wide structural diversity. The pharmacophore models were then validated by testing a set of additional known agonists. We also used competitive antagonist superpositions in order to define more precisely the topology of the mGluR1 and mGluR2 agonists' recognition site. Both models account for the activity of most potent compounds and show that the selectivity between mGluR1 and mGluR2 subtypes may be due to excluded volumes and additional binding sites, while the relative spatial position of functional groups (NH2, alpha- and gamma-CO2H) remains very similar. On both models glutamate lies in an extended form. An additional binding site is disclosed on mGluR1, while this region would be forbidden on mGluR2. This new site combines a closed and an open model for mGluR1 and accounts for the increased affinity of quisqualic acid. The models show another large hydrophobic region which is tolerated for mGluR2 and restricted for mGluR1.
Subject(s)
Glutamates/chemistry , Receptors, Metabotropic Glutamate/agonists , Animals , Binding Sites , CHO Cells , Cell Line , Cricetinae , Glutamates/metabolism , Ligands , Models, Molecular , Molecular Conformation , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
The four stereoisomers of 1-aminocyclopentane-1,3,4-tricarboxylic acid {ACPT-I (18) and -II (19), (3R, 4R)-III [(-)-20], and (3S,4S)-III [(+)-20]} have been synthesized and evaluated for their effects at glutamate receptors subtypes. ACPTs are ACPD analogues in which a third carboxylic group has been added at position 4 in the cyclopentane ring. None of the ACPT isomers showed a significant effect on ionotropic NMDA, KA, and AMPA receptors. On the other hand, ACPT-II (19) was found to be a general competitive antagonist for metabotropic receptors (mGluRs) and exhibited a similar affinity for mGluR1a (KB = 115 +/- 2 microM), mGluR2 (KB = 88 +/- 21 microM), and mGluR4a (KB = 77 +/- 9 microM), the representative members of group I, II and III mGluRs, respectively. Two other isomers, ACPT-I (18) and (+)-(3S,4S)-ACPT-III [(+)-20], were potent agonists at the group III receptor mGluR4a (EC50 = 7.2 +/- 2.3 and 8.8 +/- 3.2 microM) and competitive antagonists with low affinity for mGluR1a and mGluR2 (KB > 300 microM). Finally, (-)-(3R,4R)-ACPT-III [(-)-20] was a competitive antagonist with poor but significant affinity for mGluR4a (KB = 220 microM). These results demonstrate that the addition of a third carboxylic group to ACPD can change its activity (from agonist to antagonist) and either increase or decrease its selectivity and/or affinity for the various mGluR subtypes.