Conformationally constrained opioid peptide analogs with novel activity profiles

Novel conformationally constrained opioid peptide analogs with δ antagonist, mixed μ agonist/δ antagonist or δ agonist properties were developed. TIP(P)-related δ antagonists showed unprecedented δ antagonist potency and δ receptor selectivity, and may have potential for use in analgesia in combination with μ agonists. A definitive model of their δ receptor-bound conformation was developed. Three prototype mixed μ agonist/δ 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 δ 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.