Transformation of μ-opioid receptor agonists into biologically potent μ-opioid receptor antagonists Original Research Article

N-Allylation (–CH2–CHdouble bond; length as m-dashCH2) of [Dmt1]endomorphins yielded the following: (i) [N-allyl-Dmt1]endomorphin-2 (Dmt = 2′,6′-dimethyl-l-tyrosine) (12) and [N-allyl-Dmt1]endomorphin-1 (15) (Kiμ = 0.45 and 0.26 nM, respectively) became μ-antagonists (pA2 = 8.59 and 8.18, respectively) with weak δ-antagonism (pA2 = 6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD50 (0.148 ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P = 0.0055). Similarly, N-allylation of the potent μ-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into μ-antagonists (pA2 = 7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak δ-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics continues to provide a facile means to convert selective μ-opioid agonists into potent μ-opioid antagonists.