ABSTRACT
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
Subject(s)
Oxadiazoles/chemistry , Pyridines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Animals , Binding Sites , Central Nervous System/diagnostic imaging , Drug Evaluation, Preclinical , HEK293 Cells , Half-Life , Humans , Isotope Labeling , Male , Microsomes/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Radionuclide Imaging , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.
Subject(s)
Amides/chemistry , Piperazines/chemistry , Piperidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Amides/chemical synthesis , Amides/therapeutic use , Humans , Microsomes, Liver/metabolism , Piperazine , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
5-HT(2C) receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT(2C) receptor agonists. Since 5-HT(2C) receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT(2C) receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT(2C) agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT(2C) receptor knockout mice. Two 5-HT(2C) receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT(2C) receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT(2C) receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT(2C) receptor knockout mouse is a useful and relatively simple approach for screening 5-HT(2C) receptor ligands in vivo.
Subject(s)
Feeding Behavior/drug effects , Motor Activity/drug effects , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Aminopyridines/administration & dosage , Aminopyridines/pharmacology , Animals , Benzazepines/administration & dosage , Benzazepines/pharmacology , Dexfenfluramine/administration & dosage , Dexfenfluramine/pharmacology , Eating/drug effects , Ethylamines/administration & dosage , Ethylamines/pharmacology , Feeding Behavior/physiology , Indoles/administration & dosage , Indoles/pharmacology , Ligands , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/physiology , Naphthyridines/administration & dosage , Naphthyridines/pharmacology , Piperazines/administration & dosage , Piperazines/pharmacology , Pyrazines/administration & dosage , Pyrazines/pharmacology , Quinoxalines/administration & dosage , Quinoxalines/pharmacology , Receptor, Serotonin, 5-HT2C/genetics , Serotonin Antagonists/administration & dosage , Serotonin Receptor Agonists/administration & dosageABSTRACT
Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Drug Design , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Positron-Emission Tomography , Radioactive Tracers , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolismABSTRACT
2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.
Subject(s)
Aniline Compounds/pharmacology , Benzyl Compounds/pharmacology , Imidazolines/pharmacology , Receptor, Serotonin, 5-HT1D/metabolism , Serotonin Receptor Agonists/pharmacology , Adenylyl Cyclases/metabolism , Aniline Compounds/chemistry , Aniline Compounds/pharmacokinetics , Animals , Benzyl Compounds/chemistry , Benzyl Compounds/pharmacokinetics , Humans , Imidazolines/chemistry , In Vitro Techniques , Ligands , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Radioligand Assay , Rats , Saphenous Vein/drug effects , Saphenous Vein/physiology , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Subject(s)
Indoles/chemistry , Indoles/metabolism , Pyridines/chemistry , Pyridines/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , Humans , Ligands , Structure-Activity RelationshipABSTRACT
A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Subject(s)
Pyridines/chemistry , Receptor, Serotonin, 5-HT1B/metabolism , Receptor, Serotonin, 5-HT1D/metabolism , Humans , Ligands , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT(7) receptor ligands.
Subject(s)
Indoles/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Humans , Indoles/pharmacology , Ligands , Protein Binding , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
The human 5-HT(1B) and 5-HT(1D) receptors are especially similar in sequence despite being encoded by two distinct genes. Although, human 5-HT(1B) and 5-HT(1D) receptors have been pharmacologically differentiated using nonselective 5-HT(1B/D) receptor antagonists such as ketanserin (1), ritanserin (2) and methiothepin (3), the precise function of these receptors remains undefined, and progress toward this has been hampered by the lack of selective ligands. The interest of the major pharmaceutical companies in 5-HT(1B/1D) antagonists increased by the discovery of potent and selective tools, combined with the fact that the blockade of terminal 5-HT(1B) receptors by selective antagonists has been proposed as a new approach for more efficient and/or fast-acting antidepressant drugs, since the acute blockade of these 5-HT autoreceptors will, in theory, immediately mimic their desensitization. Furthermore, it has been also suggested that supersensitive 5-HT(1B/1D) receptors may be involved in the pathophysiology of obsessive compulsive disorders (OCD). In the 5-HT(1B/1D) agonist field, since the discovery of sumatriptan (26) (a 5-HT(1B/1D) receptor agonist) as an effective treatment for migraine headache, intensive research in this area has led to several second-generation compounds, a few of which have either entered the market place or are in late clinical trials. Beside the antimigraine activity of the 5-HT(1B/1D) agonists in clinical evaluation or already on the market, other potential therapeutic evaluations (such as gastric motor effect, bipolar disorder, autism, anti-aggressive effects) with these drugs are being investigated. This article highlights and reviews the research advances published in the 5-HT(1B/1D) antagonist and agonist literature. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT(1B/1D) agents, and on studies to understand their mechanism and pathophysiology. Emphasis is given to recent advances in the potential therapeutic applications of 5-HT(1B/1D) serotonergic agents. By no means has any attempt been made to exhaustively review the literature but rather, primary references along with citations to recent literature reviews have been included in each section.
