ABSTRACT
Recent reports have indicated that patients with schizophrenia have a profound hypo-functionality of glutamatergic signaling pathways. Positive allosteric modulation of mGlu(5) receptor has been postulated to augment NMDA function and thereby alleviate the glutamatergic hypo-function observed in schizophrenic patients. Here we report the in vitro and in vivo characterization of CPPZ (1-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone), a structurally novel positive allosteric modulator selective for mGlu(5) receptor. In HEK293 cells stably over-expressing human mGlu(5) receptor, CPPZ potentiates the intracellular calcium response elicited by a suboptimal concentration of the endogenous agonist glutamate. CPPZ does not have any intrinsic agonist activity and behaves functionally as a positive allosteric modulator. This is further supported by binding data, which demonstrate that CPPZ is able to displace the negative allosteric modulator MPEP but does not compete with the orthosteric ligand quisqualic acid. Instead, CPPZ enhances the binding of the orthosteric ligand. In native preparations, CPPZ potentiates calcium flux in rat cortical neurons stimulated with the group I agonist dihydroxyphenylglycine (DHPG). In addition, CPPZ modulates long-term potentiation in rat hippocampal slices, a process known to be NMDA dependent. In vivo, CPPZ reverses hyper locomotion triggered by the NMDA open channel blocker MK801 in CD1 mice. CPPZ was also able to reduce rat conditioned avoidance responding to electric shock. Both in vitro and in vivo data demonstrate that this novel compound acts as an mGlu(5) receptor positive allosteric modulator, which modulates NMDA dependent responses and suggests that the enhancement of mGlu(5) receptor activity may prove useful in the treatment of schizophrenia.
Subject(s)
Antipsychotic Agents/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/therapeutic use , Avoidance Learning/drug effects , Cerebral Cortex/cytology , Conditioning, Psychological/drug effects , Dizocilpine Maleate/antagonists & inhibitors , Dizocilpine Maleate/pharmacology , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Guinea Pigs , HEK293 Cells , Hippocampus/cytology , Hippocampus/physiology , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Long-Term Potentiation/drug effects , Male , Mice , Neurons/drug effects , Neurons/metabolism , Piperazine , Piperazines/metabolism , Piperazines/therapeutic use , Pyridines/metabolism , Pyridines/therapeutic use , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
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
A series of N-[(3S)-1-benzylpyrrolidin-3-yl]-(2-thienyl)benzamides 8 has been prepared and found to bind with high affinity to the human D(4) (hD(4)) and 5-HT(2A) receptors. Several compounds displayed selectivity for these receptors versus hD(2) and alpha(1) adrenergic receptors of over 500-fold.
Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Receptors, Dopamine D4/antagonists & inhibitors , Serotonin 5-HT2 Receptor Antagonists , Antipsychotic Agents/chemical synthesis , Benzamides/chemical synthesis , Dopamine/chemistry , Humans , LigandsABSTRACT
A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure-activity relationships studied. Potent ligands selective for human D(4) (hD(4)) over hD(2) and alpha(1) have been identified. One example was determined to be an antagonist in a cAMP assay, with an IC(50) of 1500 nM.
Subject(s)
Benzamides/chemical synthesis , Dopamine Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists , Benzamides/pharmacology , Dopamine Antagonists/pharmacology , Humans , Receptors, Dopamine D4 , Structure-Activity RelationshipABSTRACT
A novel series of highly potent human 5-HT(1D) agonists, dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine, was synthesized. Structure-activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K(i)=2.4 nM) agonist at the human 5-HT(1D) receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F(po)=51%).
