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Antinociceptive (aminoalkyl)indoles
M R Bell1, T E D'Ambra, V Kumar
1Department of Chemistry, Sterling Research Group, Rensselaer, New York 12144.
Journal of Medicinal Chemistry
|March 11, 1991
Summary
Pravadoline and related (aminoalkyl)indoles inhibit prostaglandin synthesis and show pain relief. Some derivatives act via prostaglandin inhibition, while others, like pravadoline, may have additional pain-relieving mechanisms.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Prostaglandins (PGs) are key mediators of inflammation and pain.
- Developing effective inhibitors of PG synthesis is crucial for pain management.
- (Aminoalkyl)indole (AAI) derivatives represent a novel class of potential PG synthesis inhibitors.
Purpose of the Study:
- To investigate the structure-activity relationships of AAI derivatives as PG synthesis inhibitors.
- To explore the antinociceptive potential of AAIs in rodent models.
- To elucidate the mechanisms underlying the antinociceptive activity of AAIs.
Main Methods:
- In vitro and ex vivo inhibition of prostaglandin synthesis in mouse brain microsomes.
- Structure-activity relationship studies, including stereochemistry and conformational analysis (NMR, UV).
- Rodent antinociceptive assays and mouse vas deferens (MVD) preparation for mechanism studies.
Main Results:
- Pravadoline (1a) and other AAIs inhibited PG synthesis, with alpha-methylation and specific stereochemistry enhancing potency.
- Conformational studies suggested differences in binding site interactions compared to arylacetic acids.
- A subset of AAIs, exemplified by 67, lacked PG inhibitory activity but demonstrated antinociceptive effects via a naloxone-independent mechanism in the MVD preparation.
- Metabolism of some AAIs yielded active acetic acid derivatives.
Conclusions:
- AAI derivatives show promise as PG synthesis inhibitors with potential antinociceptive properties.
- The antinociceptive activity of AAIs can be mediated by PG synthesis inhibition or alternative mechanisms, possibly involving MVD pathways.
- Structural modifications can decouple PG inhibition from antinociception, suggesting distinct pharmacophores for different activities.