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Synthesis and opioid activities of stereoisomers and other D-amino acid analogs of methionine-enkephalin
A series of D-amino acid-substituted analogs of the opiate peptide, methionine
5-enkephalin, were synthesized by solid-phase methods and tested for their abilities to inhibit electrically-evoked contractions of mouse vasa deferentia and to compete with tritiated enkephalin for opiate receptors on particulate fractions isolated from homogenates of rat brain. [D-Ala
2]-enkephalin and [D-Ala
2]-enkephalin amide were found to be the most potent peptides in both assay systems, being about 1000% active in the vas deferens bioassay and 120% and 150% active, respectively, in the stereospecific binding test relative to methionine
5-enkephalin itself. In comparison, [D-Met
5]-, [D-Tyr
1]-, [D-Leu
2]-, [D-Phe
2]-, [D-Ala
3]-, and [D-Phe
4]-enkephalin had not more than 10% activity. The stabilization of the β-bend conformation of methionine
5-enkephalin by the substitution of D-alanine in position 2 of the peptide chain may contribute to the high activities of the [D-Ala
2]-analogs