Design and development of new drugs for pain management

• Main Authors: Kuo-LunHuang, 黃國倫
• Other Authors: Mou-Yung Yeh
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/03806696519353714605

博士 === 國立成功大學 === 化學系碩博士班 === 101 === Pain is an unpleasant sensory and psychological experience. Although many analgesics have been used in clinical medicine, they have some side effects, such as low potency and relatively short duration of action. The aim of this dissertation was to design and develop a series of new local anesthetics and novel long-acting formulations of amitriptyline base for the treatment of pain and thermal hyperalgesia. The research efforts of this study included: evaluating the cutaneous local anesthetic actions and spinal anesthetic effect of three Class I antiarrhythmic drugs in rats, designing new local anesthetic compounds and analyzing the chemical structure-activity relationships and pharmacodynamics of these new synthetic compounds in rats, and developing a novel long-acting formulation of amitriptyline base for the treatment of thermal hyperalgesia in rats. The results of the research included: the first, all three Class I antiarrhythmic drugs (quinidine, mexiletine and flecainide) produced a dose-related cutaneous analgesia and spinal anesthesia in rats. The potencies of these drugs in producing cutaneous and spinal effects were, in ascending order, flecainide (class IC) 〉 quinidine (class IA) 〉 mexiletine (class IB). The second, new local anesthetic compounds were synthesized, developed, and evaluated the spinal anesthetic effects in rats. The intermediate chain of chemical structure of local anesthetic was carbon chain that also produced local anesthetic effect in rats, and a 5- or 6- carbon chain, indicating that their effects of spinal anesthesia were more potent. In addition, compounds N,N-diethyl-3-(2,6-dimethylphenyl)propylamine (6) and N,N-diethyl-5-(2,6-dimethylphenyl)pentylamine (17), their potencies (ED50), lethal doses (LD50), and safety indices were calculated in rats. Compound N,N-diethyl-3-(2,6-dimethylphenyl)propylamine was safer than lidocaine. The third, a novel, long-acting formulation of amitriptyline base for the treatment of thermal hyperalgesia was designed and developed. In rats, the novel depot of amitriptyline-base (100 umol/kg s.c.) had significantly longer antinociception than amitriptyline-HCl (100 umol/kg s.c.) (24 h vs. 5 h, 4.8 times longer). A single subcutaneous injection of amitriptyline-base (200 umol/kg) 1 h before spinal nerve ligation completely prevented thermal hyperalgesia in rats. In conclusion, we applied the new application of old medcations, new synthetic compounds and the improvement of dosage form to develop a series local anesthetics and long-acting analgesic for pain management.