Design, Synthesis and Biological Evaluation of Multivalent Ligands with μ/δ Opioid Agonist (μ-preferring) /NK-1 Antagonist Activities

摘要

The management of pain is a major challenge and millions of people all over the world suffer from various kinds of pain every day. Opioids continue to be the backbone for the treatment of these pain states. However, constant opioid treatment is accompanied with serious side effects. Persistent use of opioid therapy also develops analgesic tolerance in many patients. These unwanted effects significantly diminish the patients' quality of life. Sustained pain states lead to overexpression of substance P and the corresponding receptors that escalate pain [1]. Current drugs used for the treatment of pain cannot treat the prolonged pain state. It was observed that co-administrations of a 8/u opioid agonist and a neurokinin-1 (NK1) antagonist gave beneficiary results in the substance P-NK1 system in opioid signal transmission [2]. This drug cocktail showed enhanced potency in acute pain models and inhibition of opioid-induced tolerance in chronic tests using rats [3]. A study revealed that NK1 knockout mice did not show the rewarding properties of morphine. Drug combinations have restrictions as therapeutics because of poor patient compliance and difficulties in drug metabolism, distribution, and possible drug-drug interactions. Here, a new approach has been taken to combine these two different activities in one ligand which should have good metabolic and pharmacological properties [4,5]. The ligand would have potent analgesic affects in both acute pain and in neuropathic pain states without the development of unwanted side effects [6]. The present approach of our drug-design is based on the use of adjacent and/or overlapping pharmacophores, in which an opioid agonist pharmacophore is placed at the JV-terminus and the NK1 antagonist pharmacophore at the C-terminus of a single peptide derived ligand. The opioid pharmacophore of these multivalent ligands were designed based on opioid ligands, enkephalins and morphiceptin, while the NK1 pharmacophore was adopted from our early lead compound TY-032 [4]. The two pharmacophores are joined directly or by a linker/address moiety. It should be emphasized that the designed multivalent ligands have additional advantages over a cocktail of individual drugs for easy administration, a simple ADME property, and no drug-drug interactions. Earlier studies have shown that agonist activities at MOR and DOR, and antagonist activity at NK1 is beneficiary over targeting a single receptor [6]. However, it is still largely unclear what binding ratio(s) for these receptors would be ideal to achieve the desired biological profile. To address these highly challenging issues an approach has been taken to design, synthesize and evaluate in detail the biological profile of the ligands showing selectivity for MOR over DOR. As ligands with C-terminal amide showed more stability in rat plasma, we took that as reference. To enhance ligands' BBB permeability we used TV-methylated benzyl amine derivatives.