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.

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.

N-[(3S)-1-benzylpyrrolidin-3-yl]-(2-thienyl)benzamides: human dopamine D4 ligands with high affinity for the 5-HT2A receptor.

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.

N-(1-Benzylpyrrolidin-3-yl)arylbenzamides as potent and selective human dopamine D4 antagonists.

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.

Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists.

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.