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The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 May 27; Vol. 53 (10), pp. 4066-84. - Publication Year :
- 2010
-
Abstract
- As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.
- Subjects :
- Acetylcholine metabolism
Administration, Oral
Amyloid beta-Protein Precursor genetics
Animals
Antidepressive Agents chemical synthesis
Antidepressive Agents chemistry
Antidepressive Agents pharmacology
Biological Availability
CHO Cells
Cerebral Cortex metabolism
Cognition drug effects
Cricetinae
Cricetulus
Fluoxetine pharmacology
Hippocampus metabolism
In Vitro Techniques
Maze Learning drug effects
Memory drug effects
Mice
Mice, Transgenic
Microsomes, Liver metabolism
Nootropic Agents chemical synthesis
Nootropic Agents chemistry
Nootropic Agents pharmacology
Penile Erection drug effects
Piperazines chemistry
Piperazines pharmacology
Piperidines chemistry
Piperidines pharmacology
Quinolines chemistry
Quinolines pharmacology
Rats
Serotonin metabolism
Structure-Activity Relationship
Piperazines chemical synthesis
Piperidines chemical synthesis
Quinolines chemical synthesis
Serotonin 5-HT1 Receptor Antagonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20443629
- Full Text :
- https://doi.org/10.1021/jm1000908