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To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 ( 1  = Tyr-Pro-Trp-Phe-NH 2 ), the N-terminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound  3 . Tyr in compound  1  was replaced with 2,6-dimethyltyrosine yielding compound  2 . Derivative  2  was also substituted with 2-aminodecanoic acid producing compound,  4 . Lipoamino acid-modified derivatives showed improved metabolic stability and membrane permeability while maintaining high μ-opioid (MOP) receptor binding affinity and acting as a potent agonist.  In vivo  studies showed dose-dependent antinociceptive activity following intravenous (i.v.) administration of compounds  3  and  4  in a chronic constriction injury (CCI)-rat model of neuropathic pain with ED 50  values of 1.22 (±0.93) and 0.99 (±0.89) µmol/kg, respectively. Pre-treatment of animals with naloxone hydrochloride significantly attenuated the anti-neuropathic effects of compound  3 , confirming the key role of opioid receptors in mediating antinociception. In contrast to morphine, no significant constipation was produced following i.v. administration of compound  3  at 16 µmol/kg. Furthermore, following chronic administration of equi-potent doses of compound  3  and morphine to rats, there was less antinociceptive tolerance for compound  3  compared with morphine.

Lipo-Endomorphin-1 Derivatives with Systemic Activity against Neuropathic Pain without Producing Constipation