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
Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Receptor de Glutamato Metabotrópico 5/química , Tiazóis/química , Tiazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/química , Antipsicóticos/farmacologia , Niacinamida/química , Niacinamida/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Sítio Alostérico/efeitos dos fármacos , Animais , Antipsicóticos/uso terapêutico , Éteres/química , Éteres/farmacologia , Éteres/uso terapêutico , Humanos , Niacinamida/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/química , 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).
