Conformationally constrained opioid peptide analogs with novel activity profiles |
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Authors: | Peter W. Schiller, Ralf Schmidt, Grazyna Weltrowska, Irena Berezowska, Thi M.-D. Nguyen, Sé bastien Dupuis, Nga N. Chung, Carole Lemieux, Brian C. Wilkes Katharine A. Carpenter |
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Affiliation: | (1) Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada, H2W 1R7 |
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Abstract: | Novel conformationally constrained opioid peptide analogs with antagonist, mixed agonist/ antagonist or agonist properties were developed. TIP(P)-related antagonists showed unprecedented antagonist potency and receptor selectivity, and may have potential for use in analgesia in combination with agonists. A definitive model of their receptor-bound conformation was developed. Three prototype mixed agonist/ antagonists were discovered. They represent the only known compounds with this pharmacological profile and, as expected, one of them was shown to be a potent analgesic and to produce no dependence and less tolerance than morphine. Novel dipeptide derivatives turned out to be potent and selective agonists. Because of their low molecular weight and lipophilic character, these compounds may cross the blood-brain barrier and, thus, may have potential as centrally acting analgesics. |
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Keywords: | conformational restriction /content/p6336804763531r3/xxlarge948.gif" alt=" delta" align=" BASELINE" BORDER=" 0" > opioid agonists /content/p6336804763531r3/xxlarge948.gif" alt=" delta" align=" BASELINE" BORDER=" 0" > opioid antagonists mixed /content/p6336804763531r3/xxlarge956.gif" alt=" mgr" align=" MIDDLE" BORDER=" 0" > opioid agonist/ /content/p6336804763531r3/xxlarge948.gif" alt=" delta" align=" BASELINE" BORDER=" 0" > opioid antagonists opioid peptides receptor-bound conformation |
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