Unknown

Dataset Information

0

Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

ABSTRACT: The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.

SUBMITTER: Dhanya RP 

PROVIDER: S-EPMC3071440 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

Dhanya Raveendra-Panickar RP   Sidique Shyama S   Sheffler Douglas J DJ   Nickols Hilary Highfield HH   Herath Ananda A   Yang Li L   Dahl Russell R   Ardecky Robert R   Semenova Svetlana S   Markou Athina A   Conn P Jeffrey PJ   Cosford Nicholas D P ND  

Journal of medicinal chemistry 20101214 1

The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacoki  ...[more]

Similar Datasets

Unknown The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats.
| S-EPMC2922422 | biostudies-literature
Unknown VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
| S-EPMC4702078 | biostudies-literature
Unknown Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology.
| S-EPMC3629835 | biostudies-literature
Unknown The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys.
| S-EPMC4529372 | biostudies-literature
Unknown Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.
| S-EPMC4690453 | biostudies-literature
Unknown Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias.
| S-EPMC5341252 | biostudies-literature
Unknown Administration of the metabotropic glutamate receptor subtype 5 allosteric modulator GET 73 with alcohol: A translational study in rats and humans.
| S-EPMC7014573 | biostudies-literature
Unknown Population Pharmacokinetic and Exposure-dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients.
| S-EPMC6132363 | biostudies-literature
Unknown Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.
| S-EPMC6420870 | biostudies-literature
Unknown Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats.
| S-EPMC5555082 | biostudies-literature