Pharmacological agents acting at subtypes of metabotropic glutamate receptors.

Metabotropic (G-protein-coupled) glutamate (mGlu) receptors have now emerged as a recognized, but still relatively new area of excitatory amino acid research. Current understanding of the roles and involvement of mGlu receptor subtypes in physiological/pathophysiological functions of the central nervous system has been recently propelled by the emergence of various structurally novel, potent, and mGlu receptor selective pharmacological agents. This article reviews the evolution of pharmacological agents that have been reported to target mGlu receptors, with a focus on the known receptor subtype selectivities of current agents.     

In silico approaches towards the understanding of the structure-function relationships in metabotropic glutamate receptors (mGluRs) and other family C GPRCs

Family C of the superfamily of G-protein coupled receptors is a growing family of heptahelical receptors, which includes, among others, metabotropic glutamate receptors (mGluRs) and GABA(B) receptors. A common feature of all the members of family C is a structural architecture much more complex than any other GPCRs. Computational studies, including homology modeling, pharmacophore definitions and molecular dynamics simulations have constantly flanked experimental approaches in the understanding of the receptor functioning. The present review will discuss the evolution of our perception in family C GPCRs structure and function as emerged from the critical comparison of in silico methods with molecular biology and crystallographic experiments.     

Metabotropic glutamate receptors (mGluRs) and diabetic neuropathy

Multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) cause neuronal cell death through either necrosis or apoptosis. However, recently alternative evidence has shown that mGluRs have modulatory effects on excitotoxicity and neuronal cell death. Metabotropic glutamate receptors form a family of eight subtypes (mGluR1-8), subdivided into three groups (I-III) that initiate their biological effects by G protein-linked intracellular signal transduction. Their expression throughout the mammalian nervous system implicates these receptors as essential mediators of a cell's fate during injury to the nervous system. Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) has been established to be neuroprotective in vitro and in vivo. In contrast, group-I mGluRs (mGluR1 and -5) need to be antagonized in order to evoke protection. The pathological signaling pathways associated with diabetic neuropathy are complex and this influences development of appropriate therapies. The Group II mGluRs target several signaling pathways affected in diabetic neuropathy, prevent cellular injury in the peripheral nervous system, and may provide a novel mechanism for treatment of diabetic neuropathy. Direct or indirect activation of mGluR2/3 in animal models protects against development of diabetic neuropathy. The potential mechanisms and role of mGluRs in protection against diabetic neuropathy will be reviewed.     

Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes.

1. We investigated the agonist and antagonist activities of 22 new phenylglycine and phenylalanine derivatives for metabotropic glutamate receptors (mGluRs) by examining their effects on the signal transduction of mGluR1, mGluR2 and mGluR6 subtypes expressed in Chinese hamster ovary cells. This analysis revealed several structural characteristics that govern receptor subtype specificity of the agonist and antagonist activities of phenylglycine derivatives. 2. Hydroxyphenylglycine derivatives possessed either an agonist activity on mGluR1/mGluR6 or an antagonist activity on mGluR1. 3. Carboxyphenylglycine derivatives showed an agonist activity on mGluR2 but an antagonist activity on mGluR1. 4. alpha-Methylation or alpha-ethylation of the carboxyphenylglycine derivatives converts the agonist property for mGluR2 to an antagonist property, thus producing antagonists at both mGluR1 and mGluR2. 5. Structurally-corresponding phenylalanine derivatives showed little or no agonist or antagonist activity on any subtypes of the receptors. 6. This investigation demonstrates that the nature and positions of side chains and ring substituents incorporated into the phenylglycine structure are critical in determining the agonist and antagonist activities of members of this group of compounds on different subtypes of the mGluR family. 7. We also tested two alpha-methyl derivatives of mGluR agonists. (2S, 1'S, 2'S)-2-(2-Carboxycyclopropyl)glycine (L-CCG-I) is a potent agonist for mGluR2 but alpha-methylation of this compound changes its activity to that of an mGluR2-selective antagonist. In contrast, alpha-methylation of L-2-amino-4-phosphonobutyrate (L-AP4) results in retention of an agonist activity on mGluR6. Thus, alpha-methylation produces different effects, depending on the chemical structures of lead compounds and/or on the subtype of mGluR tested.     

Photoswitchable allosteric modulators for metabotropic glutamate receptors

Metabotropic glutamate receptors (mGlu) are a family of class C G protein-coupled receptors (GPCRs) with important biological functions and widespread expression. The mechanisms of mGlu activation and the development of allosteric modulators for these dimeric proteins have attracted singular attention including the use of light regulated ligands. Photopharmacology involves the integration of a photoactive moiety into the ligand structure that following specific illumination undergoes a structural rearrangement and changes its biological activity. The use of light-regulated allosteric ligands offers the opportunity to manipulate mGlu signalling with spatiotemporal precision, unattainable with classical pharmacological approaches. In this review, we will discuss some of the innovations that have been made in the allosteric photopharmacology of mGlu receptors to date. We discuss the prospects of these molecular tools in the control of mGluRs and the new perspectives in understanding mGlu mechanisms, pharmacology and (patho)physiology that can ultimately result in innovative drug discovery concepts.     

Evaluation of agonists and antagonists acting at Group I metabotropic glutamate receptors in the thalamus in vivo.

Recordings were made from single neurones in the ventrobasal thalamus of anaesthetised rats in order to evaluate the properties of several agonists and antagonists of Group I mGlu receptors. The selective mGlu1 receptor antagonist LY367385 was found to reduce excitatory responses to iontophoretically applied ACPD and DHPG whereas the mGlu5 agonist CHPG was resistant to antagonism. The antagonists LY367366 and LY393053 reduced responses to all three agonists, but without reducing responses to NMDA or AMPA. Although AIDA was also found to reduce mGlu agonist-evoked responses, this antagonist also produced significant reductions in responses to NMDA and AMPA. These data suggest that there are functional mGlu1 and mGlu5 receptors in the thalamus. Furthermore, LY367385 is a useful tool for investigating mGlu1 functions whereas LY367366 and LY393053 have a broader spectrum of action. The usefulness of AIDA as an antagonist in physiological experiments would appear to be limited by its effects against NMDA and AMPA.     

New therapeutic frontiers for metabotropic glutamate receptors

Our understanding of glutamatergic transmission in the central nervous system has been greatly expanded with the discovery and investigation of the metabotropic glutamate receptor family. Complementing the ionotropic glutamate-gated ion channels, these G-protein coupled receptors play critical roles in neuronal and glial functions such as the modulation of neuronal excitability, synaptic transmission, and various metabolic functions. Because of the ubiquitous distribution of glutamatergic synapses, it has been deemed likely that mGlu receptors participate in most, if not all, major functions of the CNS. It is predicted that the wide diversity and heterogeneous distribution of mGlu receptor subtypes will provide avenues to develop clinically relevant pharmacological agents that target specific CNS systems. mGlu receptors are regulated by differences in expression, alternative splicing patterns, and interactions with other proteins in the cell and it is anticipated that an understanding of these modifiers of mGlu receptor function will open new opportunities for pharmacological tool development and new therapeutic strategies. Over the past decade, an increasing number of selective agonists, antagonists, and allosteric modulators have been developed which target distinct mGlu receptor subtypes; many of these agents have now been further validated in numerous electrophysiological and behavioral models. The combination of these pharmacological tools, in conjunction with genetic approaches, has led to major advances in our understanding of the roles of mGlu receptors in the regulation of CNS function and animal behavior. These studies suggest the exciting possibility that drugs active at mGlu receptors will be useful in treatment of a wide variety of neurological and psychiatric disorders such as Parkinson's disease, anxiety disorders, and schizophrenia.     

Structure-activity relationships for anticholinergic morpholinium derivatives.

The anticholinergic activity of a series of morpholinium derivatives was studied by means of the Free-Wilson method. The importance of steric and lipophilic effects is pointed out.     

Structure-activity relationships of glutamate carboxypeptidase II (GCPII) inhibitors

Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a zinc metallopeptidase that hydrolyzes N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate in the nervous system. Inhibition of GCPII has the potential to reduce extracellular glutamate and represents an opportune target for treating neurological disorders in which excess glutamate is considered pathogenic. Furthermore, GCPII was found to be identical to a tumor marker, prostate-specific membrane antigen (PSMA), and has drawn significant interest as a diagnostic and/or therapeutic target in oncology. Over the past 15 years, tremendous efforts have been made in the discovery of potent GCPII inhibitors, particularly those with phosphorus-, urea- and thiol-based zinc binding groups. In addition, significant progress has been made in understanding the three-dimensional structural characteristics of GCPII in complex with various ligands. The purpose of this review article is to analyze the structure-activity relationships (SAR) of GCPII inhibitors reported to date, which are classified on the basis of their zinc-binding group. SAR and crystallographic data are evaluated in detail for each of these series to highlight the future challenges and opportunities to identify clinically viable GCPII inhibitors.     

Arylpiperazine derivatives acting at 5-HT(1A) receptors

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists. Among 5-HTRs, the 5-HT(1A) subtype is the best studied and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT(1A)R sites. Among these, arylpiperazine derivatives represent one of the most important classes of 5-HT(1A)R ligands. This article will review the development of arylpiperazine derivatives acting at 5-HT(1A)Rs with an emphasis on structure-affinity relationships of agonists and antagonists, ligand-receptor interactions and pharmacological applications.     

Structure-activity relationships in a series of bisquaternary bisphthalimidine derivatives modulating the muscarinic M(2)-receptor allosterically

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are well-established ligands of the common allosteric binding site of muscarinic M(2) receptors. Previous structure-activity relationships (SAR) revealed two positively charged centers and two lateral phthalimide moieties in a defined arrangement to be essential of a high allosteric potency. The purpose of this study was to replace one carbonyl group of the phthalimides with hydrogens, hydroxy, alkoxy, phenyl, benzyl, and benzylidene groups in order to check the influence of these substituents on the allosteric activity in antagonist-linked receptors. The analysis of the quantitative SAR indicated that a high allosteric potency is related to a certain amount of rigidity as well as polarizibility and the ability to form hydrophobic interactions.     

Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives

A series of analogues of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length, and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the alpha 1-adrenergic antagonist [3H]WB-4101. Compounds were also tested in vivo for tranquilizing properties and induction of catalepsy. Potency at the [3H]spiperone binding site was affected by alkylene chain length and imide portion composition. Nonortho substituents on the aryl moiety had little effect on [3H]spiperone binding affinity. Structure-activity relationships of ortho substituents demonstrated only modest correlations between the receptor binding data and physical parameters of the substituents. The complex nature of the drug-receptor interactions may be understood in terms of the fit of buspirone to a hypothetical model of the dopamine receptor.     

Piperidinediones, III. Structure-activity relationships of the enantiomers of a series of 2,6-piperidinedione derivatives

Among the racemic 2,6-piperidinediones 1 – 6 , compound 6 has the highest anesthetic activity. The enantiomers of 1, 2, 4 and 5 possess different anesthetic potencies depending on the nature of the aliphatic side chain. The S(-)-enantiomers of the piperidinediones 2, 3 and 5 cause initial CNS stimulation with convulsive symptoms followed by anesthesia.     

Targeting of metabotropic glutamate receptors for the treatment of schizophrenia

The glutamatergic system is involved in a wide range of physiological processes in the brain, and its dysfunction plays an important role in the etiology and pathophysiology of psychiatric disorders, including schizophrenia. Among the glutamate receptors, metabotropic receptors (mGlu receptors) have emerged as attractive therapeutic targets for the development of novel interventions for psychiatric disorders. Among them, group II mGlu receptors, such as mGlu2 and mGlu3 receptors, are of particular interest because of their unique distribution and the regulatory roles they have in neurotransmission. Recently, potent agonists for mGlu2/3 receptor have been synthesized, and their pharmacological roles have been intensively investigated in animal models. The efficacy for the treatment of schizophrenia has also been proven in a clinical trial. Recently, much attention has been paid to mGlu2 receptor potentiators, which potentiate the glutamate response without affecting the actual activity of the mGlu2 receptor. In addition, mGlu1 receptor antagonists have recently been proposed as an attractive approach to developing novel antipsychotics in animal models. This review describes the potential of both mGlu2/3 receptor agonists/potentiators and mGlu1 receptor antagonists for the treatment of schizophrenia.