Preparation and opioid activity of analogs of the analgesic dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide

A number of analogues of the recently disclosed analgesic dipeptide 2,6-dimethyl-L-tyrosyl-D-alanine-phenylpropylamide (SC-39566, 2) were prepared. These analogues contained oxymethylene, aminomethylene, ketomethylene, bismethylene, and trans double bond (including vinyl fluoride) isosteric replacem...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-01, Vol.35 (2), p.223-233
Main Authors: Chandrakumar, Nizal S, Yonan, Peter K, Stapelfeld, Awilda, Savage, Michael, Rorbacher, Elaine, Contreras, Patricia C, Hammond, Donna
Format: Article
Language:English
Subjects:
Analgesics, Opioid - chemical synthesis
Analgesics, Opioid - metabolism
Analgesics, Opioid - pharmacology
Animals
Brain - metabolism
Chemistry
Dipeptides - chemical synthesis
Dipeptides - metabolism
Dipeptides - pharmacology
Exact sciences and technology
In Vitro Techniques
Male
Mice
Organic chemistry
Pain Measurement - methods
Peptides
Preparations and properties
Rats
Receptors, Opioid - metabolism
Structure-Activity Relationship
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Summary:A number of analogues of the recently disclosed analgesic dipeptide 2,6-dimethyl-L-tyrosyl-D-alanine-phenylpropylamide (SC-39566, 2) were prepared. These analogues contained oxymethylene, aminomethylene, ketomethylene, bismethylene, and trans double bond (including vinyl fluoride) isosteric replacements for the amide bond between the D-alanine and phenylpropylamine units in 2. These compounds were tested in opioid binding assays and in the mouse writhing assay for analgesic activity. Though not as potent as 2, the oxymethylene, and trans double bond isosteres showed analgesic activity. The aminomethylene analogues also showed binding activity in subnanomolar concentrations at the mu receptor. The amide bond between 2,6-dimethyl-L-tyrosine and D-alanine units seems to be critical for opioid activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00080a005