RESUMO
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
Assuntos
Acetileno/farmacologia , Ácidos Picolínicos/farmacologia , Receptor de Glutamato Metabotrópico 5/agonistas , Acetileno/síntese química , Acetileno/química , Regulação Alostérica/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Ligação Competitiva , Membrana Celular/metabolismo , Descoberta de Drogas/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Masculino , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Estrutura Terciária de Proteína , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/química , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 µM and is inactive against mGlu(5).
