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[摘要]：This letter describes the discovery, structure-activity relationship, and in vitro and in vivo pharmacological profile of a novel non-MPEP-derived mGluR(5) positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGluR(5) chemotyper exhibits the ability to act as either a noncompetitive antagonist/negative allosteric modulator or a potentiator of the glutamate response, depending on the identity of the amide substituent, that is, a molecular switch". A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGluR(5) receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of antipsychotic activity, thus providing the first example of a centrally active mGluR(5) PAM optimized from an HTS-derived mGluR(5) noncompetitive antagonist. |
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