Jalaj Arora

Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator

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.

5,5-diaryl-2-amino-4-pentenoates as novel, potent, and selective glycine transporter type-2 reuptake inhibitors

A novel series of 5,5-diaryl-2-amino-4-pentenoates was synthesized and found to be potent and selective glycine transporter type-2 reuptake inhibitors.

4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators

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.

Novel serotonergic and non-serotonergic migraine headache therapies

In the last four years discovery of pharmacotherapeutic treatments for migraine headaches has received much attention. Since the patent literature was last reviewed in 1997 [1], advances have been made in the understanding of mechanism and pathophysiology of migraine. Introduction of sumatriptan to the market has led to acceleration in research efforts towards finding safe and effective treatments for migraine. The importance of this field is evidenced by the number of compounds in clinical trials and by the number of patents filed in recent years. For example, besides sumatriptan, a second generation of three new drugs (naratriptan [2], zolmitriptan [3] and rizatriptan [4]) has entered the marketplace and few others are presently in clinical evaluation. In addition, classical drug design has yielded highly potent and selective ligands to target relevant receptor subtypes in migraine treatment. This article highlights and reviews the research advances published in patent literature between January 1997 through November 2000. The article is supplemented with selected references on design and development of novel agents with which to treat migraine and to study its mechanism and pathophysiology. Emphasis is made on serotonergic agents, namely seratonin (5-hydroxytryptamine, 5-HT) receptor subtype (5-HT1D, 5-HT1F and 5-HT5) agonists, drug combinations (e.g., 5-HT1D agonists with COX-2 inhibitors or NSAIDs), tachykinin receptor (NK1) antagonists and GABAergic agents. Also included are patents describing chemical entities that may be effective in migraine therapy based on their pharmacological actions as anticonvulsants, LTD4 receptor blocker agents and thromboxane inhibitors. By no means has any attempt been made to exhaustively review the literature; but rather, primary references along with citations to latest literature reviews have been included in each section.