The Pharmacological Study Of μ/δ/κ Opioid Receptor Triple Agonists

Opioid receptor drugs are the most frequently used analgesics, it have been long-lasting applied to the treatment of the pain since the discovery. There are four types of opioid receptors, μ-(MOR), δ-(DOR), κ-(KOR) and opioid receptor-like 1 (ORL-1), which belongs to G-protein-coupled receptor(GPCR) superfamily.Opioid drugs include natural, semisynthetic and synthetic opioid drugs. Classical opioid drugs can selectively activate MOR and have wide spectrum of anti-pain, however, the severe side effects, such as tolerance, respiratory depression, dependence, constipation and urinary retention, have greatly restrict the clinical application. Over the past decades, amount of research have been done in molecular pharmacological mechanism of opioids and opioid receptors in order to design the novel analgesic compounds with less or even no side effects, the research have shown that the subtype of opioid receptors have mutual structural or functional effect(i.e.. μ/8/κ/ORL-1 recptors). However, there are no effective methods to solve those side effects of opiate.BW373U86 is a small molecular receptor agonist which was firstly designed by Prof. Kwen-jen Chang. Although BW373U86 have less analgesic effect, it could against the muscular anchylose and respiratory depression caused by　μ receptor. Based on the structure of BW373U86, we further optimize the configuration, and then get a array of δ/μ/κ receptor mixture agonists. Of these compounds, we found that DPI-3290 and DPI 125 had higher stimulation of　μ and 8 receptor, and lower stimulation of κ receptor. Both of them have higher analgesia effect as well as lower respiratory deression and dependence. In addition, the safety ratio of respiratory depression were higher than fentanyl and morphine.Because of these characters, we further designed the novel diarylmethylpiperazine derivations by allocation the proportion in activation ability of μ,δ,κ receptor and investigated the effects of proportion in activation ability of μ,δ κ receptor on the pharmacological response of compounds. These work will be contribute to tap the perfect compounds with ideal analgesia effect and low toxicity, and the research works are carried out as follow:ObjectiveThis study we investigated was based on the diarylmethylpiperazine derivations like KUST101, KUST102, KUST201 and KUST202, and then evaluated the pharmacodynamics of four compounds on antinociceptive effects and the potential dependence and tolerance effect, which provide the theoretic and empirical data for tapping the strong analgesic effect and low toxicity compounds.MethodDiarylmethylpiperazine derivations like KUST101, KUST102, KUST201, KUST202 were used to evaluate the dose-response relationship and time-response relationship by tail-pinch and hot plate test in rats.Then the tolerance of these four compounds were evaluated in the mouse/rat tail-pinch test and 55℃ hot-plate test with continuous injection. Besides, the physical dependence of these four compounds were evaluated in the naloxone-precipitated withdrawal sign.Result1. The outcome shows that the antinociceptive ED50 of diarylmethylpiperazine derivations like KUST101, KUST102, KUST201 and KUST202 were 0.3,2.22,0.34 and 1.45mg/kg in tail-pinch test in rats, however, the antinociceptive ED50 of diarylmethylpiperazine derivations like KUST101, KUST102, KUST201 and KUST202 were 6.04,10.23,0.68 and 8.43 mg/kg in hot plate test in rats.2. Chronic treatment of KUST101, KUST102, KUST201 and KUST202 could result in acute tolerance and chronic tolerance. In the experiment, the maximal percent of effect reached 100%, which was higher than the combination of compounds and NT1. The reason is that these four compounds are δ/μ/κ triple agonist of opioid receptor, and the combination of δ and μ agonist can increase the antinociceptive effects of μ opioid receptor, which facilitated the development of the tolerance.3. The signs of naloxone-precipitated withdrawal abstinence, such as jumping, wet-dog shake, were obvious observed by increasing the dose of KUST101, KUST102, KUST201 and KUST202, and the symptoms of the withdrawal abstinence would increase significantly as the dose increased.ConclusionThe results in vivo and in vitro show that KUST101, KUST102, KUST201 and KUST202 are multi-subtype opioid receptors agonists and evaluate the pharmacodynamics systematacially. The four compounds all have antinociceptive effects, physical and psychological dependence, and they have different stimulation of μ-,δ-, and κ-opioid receptor. Obviously, the antinociceptive effects of KUST201 are superior to the others, physical dependence of KUST101 is lower than the others. The four compounds are effective in curing the pain but the side effects, such as tolerance, respiratory depression, constipation, have greatly restrict their application. These four compounds are not the ideal analgesic with high-efficient and low-side effect, but these studies provides us with a practical evaluation system to further analyse the relationship between subtybe-opioid receptor and activity.