Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): Efficacy in an animal model for schizophrenia

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 18, 2005, Pages 4068-4072

  Govek, Steven P ^a   Bonnefous, Celine ^a   Hutchinson, John H ^a   Kamenecka, Theodore ^a   McQuiston, Jeffrey ^a   Pracitto, Richard ^a   Zhao, Lucy X ^a   Gardner, Michael F ^a   James, Joyce K ^a   Daggett, Lorrie P ^a   Rowe, Blake A ^a   Schaffhauser, Hervé ^a   Bristow, Linda J ^a   Campbell, Una C ^a   Rodriguez, Dana E ^a   Vernier, Jean Michel ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Allosteric potentiator; Metabotropic glutamate receptor; mGlu2; mGluR2; Schizophrenia

Indexed keywords

INDOLE; METABOTROPIC RECEPTOR AGONIST; PYRROLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; IN VIVO STUDY; NONHUMAN; RAT; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION;

ACETOPHENONES; ALLOSTERIC REGULATION; ANIMALS; BRAIN; CROSS-LINKING REAGENTS; DISEASE MODELS, ANIMAL; HUMANS; KETAMINE; MOLECULAR STRUCTURE; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; SCHIZOPHRENIA; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 23644453431     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.06.017     Document Type: Article

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26. 50 was generally <2-fold and the difference in percentage potentiation was generally <15% with respect to the values quoted in the tables
27. Compound 1 was inactive up to 10 μM at mGluR3 as well as mGluRs 1, 4, 5, 7, and 8
28. Sprague-Dawley rats; 2 mpk IV (n = 2); 10 mpk PO (n = 3)
29. B/P = ratio of brain level to plasma level
30. All compounds were synthesized by methods previously described by us (Ref. 10). For installation of the C4 propyl group see: Moody C. J. J. Chem. Soc., Perkin Trans. 1 1984, 1333. All final compounds displayed spectral data (NMR, MS) that were consistent with the assigned structure
31. See Refs. 10a,b for general SAR; results with neo-pentyl are not published
32. 35S]GTPγS binding assay (see Ref. 11). All compounds except 9 were inactive up to 10 μM
33. A compound containing the cis-olefin was made in a related series and showed no activity
34. In healthy humans, ketamine induces behavioral disruptions and cognitive deficits that mimic some aspects of schizophrenia. Similar behavioral disruptions, typified by increased locomotion (hyperactivity), are seen in ketamine-treated rodents. This model assesses the effect of a compound on the locomotion of ketamine-treated animals. See Ref. 4