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Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Nov 26; Vol. 55 (22), pp. 9434-45. Date of Electronic Publication: 2012 Oct 23. - Publication Year :
- 2012
-
Abstract
- Compounds that modulate metabotropic glutamate subtype 2 (mGlu(2)) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu(2) receptor positive allosteric modulators (PAMs). The effects of N-substitution (R(1)) and substitutions on the aryl ring (R(2)) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu(2) receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
- Subjects :
- Administration, Oral
Allosteric Regulation
Animals
Behavior, Animal drug effects
Brain metabolism
Glutamic Acid metabolism
HEK293 Cells
Humans
Indoles chemistry
Indoles pharmacokinetics
Microsomes, Liver drug effects
Microsomes, Liver metabolism
Molecular Structure
Nicotine administration & dosage
Rats
Structure-Activity Relationship
Tissue Distribution
Tobacco Use Disorder metabolism
Brain drug effects
Indoles pharmacology
Receptors, Metabotropic Glutamate agonists
Tobacco Use Disorder drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23009245
- Full Text :
- https://doi.org/10.1021/jm3005306