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Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity.
La, Daniel S; Salituro, Francesco G; Martinez Botella, Gabriel; Griffin, Andrew M; Bai, Zhu; Ackley, Michael A; Dai, Jing; Doherty, James J; Harrison, Boyd L; Hoffmann, Ethan C; Kazdoba, Tatiana M; Lewis, Michael C; Quirk, Michael C; Robichaud, Albert J.
Afiliación
  • La DS; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Salituro FG; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Martinez Botella G; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Griffin AM; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Bai Z; Wuxi AppTec , 288 Fute Zhong Road , Shanghai 200131 , China.
  • Ackley MA; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Dai J; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Doherty JJ; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Harrison BL; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Hoffmann EC; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Kazdoba TM; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Lewis MC; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Quirk MC; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
  • Robichaud AJ; SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
J Med Chem ; 62(16): 7526-7542, 2019 08 22.
Article en En | MEDLINE | ID: mdl-31390523
Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de N-Metil-D-Aspartato / Regulación Alostérica / Neuroesteroides Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de N-Metil-D-Aspartato / Regulación Alostérica / Neuroesteroides Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos