Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-L-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47) and [N-allyl-Dmt1]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier. 1. Introduction Morphine, which represents the quintessential agonist for μ-opioid receptor, has been used as a pain-killing drug for millennia. Since natural occurring opioid antagonists are nonexistent, naloxone and naltrexone were derived from morphine and currently find use in drug addiction and alcohol cessation programs; however, these alkaloid-derived antagonists exhibit numerous deleterious side effects. In 1975, the endogenous opioid peptides enkephalins (H-Tyr-Gly-Gly-Phe-Met-OH/Leu-OH) were discovered [1], followed sequentially by the endorphins [2], dynorphins [3], and the endomorphins [4], all of which are involved in the modulation and attenuation of pain and regulation of homeostatic mechanisms. Of the endogenous opioid peptides, endomorphin-1 (EM-1: H-Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (EM-2: H-Tyr-Pro-Phe-Phe-NH2) exhibited high μ-opioid receptor affinity (Ki = 0.36 and 0.69？nM, resp.) with high selectivity: 4,000- and 13,000-fold preference over the δ-opioid receptor and a similar 15,000- and 7,500-fold preference for μ-receptor relative to κ-opioid
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