Effects of Methyl and Halogens in Analgesic Peptide Molecules for Their Potent Agonist Activities at MOR/DOR and Antagonist Activity at NK1R

Treating pain has been always challenging, especially when it becomes chronic in nature. Current drugs (e.g. opioid drugs) cannot treat this problem effectively. In addition, constant use of these drugs has deadly side effects including drowsiness and mental clouding, nausea and emesis, and constipation [1]. Development of analgesic tolerance and hyperalgesia in many patients as the results of taking these drugs are also a serious concern. Overexpression of substance P and its receptor has been observed during prolonged pain states. Studies revealed that co-administration of cocktails of drugs containing μ/δ opioid agonist and NK1 antagonist can provide better analgesic effects in rat model while reducing side effects [2-4]. Herein, we report design, synthesis and SARs of few multifunctional ligands having μ/δ opioid agonist (μ-preferring) and NK1 antagonist activities. The detail of this study has already been communicated to J. Med. Chem. for publication [5]. We anticipate that these ligands will show better analgesia while reducing the adverse side effects. Our drug design principle is based on overlapping and adjacent pharmacophores (Figure 1) and we considered our previously published μ-selective (binding) ligand TY012 (H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bn(3ʹ,5ʹ-(CF3)2)) [6].