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

<div><p>To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 (<b>1</b> = Tyr-Pro-Trp-Phe-NH₂), the N-terminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound <b>3</b>. Tyr in compound <b>1</b> was replaced with 2,6-dimethyltyrosine yielding compound <b>2</b>. Derivative <b>2</b> was also substituted with 2-aminodecanoic acid producing compound, <b>4</b>. 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. <em>In vivo</em> studies showed dose-dependent antinociceptive activity following intravenous (i.v.) administration of compounds <b>3</b> and <b>4</b> in a chronic constriction injury (CCI)-rat model of neuropathic pain with ED₅₀ 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 <b>3</b>, 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 <b>3</b> at 16 µmol/kg. Furthermore, following chronic administration of equi-potent doses of compound <b>3</b> and morphine to rats, there was less antinociceptive tolerance for compound <b>3</b> compared with morphine.</p>