Developmental Potential for Endomorphin Opioidmimetic Drugs

Abstract

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.

An Engineered Endomorphin-2 Gene for Morphine Withdrawal Syndrome

“…After cessation of external opioids, the addict enters an acute withdrawal syndrome due to the shortage of endogenous opioid. Compensation of opioids, such as enkephalins [ 34 ], β-endorphin [ 35 ] and endomorphin [ 36 ], have shown potential applications in treatment of dependence. Using trans-gene technique, dependence related protein such β-endorphin and Cocaine Hydrolase, have been transducted into central nervous system and shown the attenuation of dependence, which results suggest that transduction of substantial mounts of an engineered human protein in or near the cells that are affected in dependence could directly alter the pathophysiologic state [ 37 , 28 ].…”