A series of 6-amino acid conjugates (glycine, alanine and phenylalanine) of the highly potent opioid analgesic 14-O-methyloxymorphone was developed in an effort to obtain agonists that would have potentially limited ability to cross the blood-brain barrier. Binding studies revealed that all derivatives displayed high affinities (0.77-2.58 nM) at the μ-opioid receptor in rat brain membranes. They were potent agonists in mouse vas deferens preparation (IC50=5.52-26.8 nM). While the α-amino acid epimers are favoured by μ-opioid receptors, the β-epimers proved to have increased interaction with δ-sites. Only the β-phenylalanine conjugate showed some preference for δ- over μ-opioid receptors and δ-opioid receptor agonist activity. The relatively high δ-opioid receptor affinity of this analogue was also predicted by molecular modelling studies. The newly developed ionizable derivatives could find clinical applications as potent analgesics without the adverse actions of centrally acting opioids.
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