Design,Synthesis And Biological Activity Evaluation Of Novel Bifunctional Anti-neuropathic Pain Drugs Based On σ₁R And MOR

Neuropathic pain is a chronic pain,which causes patient disability,and reduces quality of life,as well as productivity.Currently,drugs for treating neuropathic pain include antidepressants,anticonvulsants,and opioid drugs.Unfortunately,these drugs have many disadvantages,such as limited types of drugs,off-label drug use,limited efficacy,and a range of side effects.Therefore,a large unmet medical need exists in the treatment of neuropathic pain,and adequate pain management constitutes an important clinical challenge.Sigma-1 receptor（σ₁R）antagonists could be used for treating neuropathic pain.To date,noσ₁R antagonist analgesics have been introduced to the market.σ₁R as a chaperone protein participates in the regulation of mu opioid receptor（MOR）analgesic mechanism,and its antagonists can increase the analgesic effect of opioids.Innovative anti-neuropathic pain drug with bifunctional ofσ₁R and MOR is a hot research field.The main research contents of this dissertation are as follows:A new series of piperidine amide derivatives were designed based on the principles of pharmacophore fusion,docking analysis and molecular hybridization.All of compounds were synthesized and confirmed by nuclear magnetic resonance（NMR）and mass spectrometry（MS）.Affinities forσ₁R and MOR were evaluated by radioligand binding tests in vitro and structure–activity relationship（SAR）was discussed in detail.Twenty compounds with bifunctional activity ofσ₁R and MOR were obtained.Analgesic effects of the above-mentioned preferred compounds were evaluated in formalin test,chronic constriction injury（CCI）neuropathic pain model,acetic acid writhing test,and hot plate test.Compounds HKC-082 and HKC-083 showed powerful dose dependent analgesic effects in these four pain models.Additionally,the safety was preliminarily evaluated by receptor selectivity test and acute toxicity test.Both compounds HKC-082 and HKC-083 had good receptors selectivity and high LD₅₀ value.The biological activity of enantiomers of compound HKC-082 was further studied.Compound HKC-126（S）asσ₁R antagonist and MOR agonist showed a stronger analgesic effect than the racemate HKC-082 and（R）configuration enantiomer HKC-127.Then,safety profiles of compound HKC-126 were evaluated in rotating rod,autonomous activity,small intestinal transport inhibition,naloxone-induced withdrawal jump,conditioned place preference（CPP）,and whole-body plethysmography（WBP）test.In contrast to an equianalgesic dose of fentanyl,compound HKC-126 produced fewer opioid-like side effects,such as reward liability,respiratory depression,physical dependence,sedation;and had no motor neurotoxicity.Finally,the pharmacokinetic profiles of compound HKC-126 were determined in SD rats,which revealed the characteristics of rapid absorption,short half-life,and high bioavailability after subcutaneous injection.In summary,compound HKC-126 has potential for treating neuropathic pain.This dissertation will provide a theoretical and experimental basis for the future research of novel analgesics based on the dual target ofσ₁R and MOR for treating neuropathic pain.