Applications Of Nuclear Technology In New Drug Research

Ligustrazine (chemical structure: tetramethylpyrazine, TMP), one of the main active principles from the traditional Chinese herb Ligusticum Wallichii Franch (CHUANXIONG), has been widely used in China as a safe and effective drug for the treatment of occlusive cardiovascular and cerebrovascular diseases as well as chronic cardiopulmonary diseases. However, in the recent years, it has been reported that the drug metabolizes too rapidly and its effects disappear too fast So it is of importance both clinically and theroetically to study the structure activity relationship (SAR) of TMP and to modify its chemical structure in order to develop TMP anologues of high potency with longer effective half-life and higher bioavailability.Firstly, the metabolism and biotransformation of TMP both in healthy subjects and rats were studied by using gas chromatograph/mass spectrometry/computer system and the deuterium as a tracer. TMP itself and its six metabolites were identified from the urine, blood and organs of rats (and also from human volunteers). The results indicated that the major metabolic pathways of TMP in vivo consisted of the oxidation of methyl groups on the pyrazine ring.Various deuterated TMPs, such as 6D-TMP ( 6 atoms of H in TMP replaced by D), 12D-TMP ( all H atoms in TMP replaced by D ) were synthesized with the purpose of blocking or slowing down the speed of TMP oxidation metabolism. Systematic pharmacological experiments were performed to invesitgate isotope effects of deuterated TMP. In vivo and in vitro studies showed that:(1) Both 12D-TMP and 6D-TMP exhibited significant antithrombotic effects on the rabbit's jugular vein thrombus, double labeled with ¹³¹I and ¹²⁵I. This quantitative and convenient method of using double labeling technique was first devised by our lab.(2) Deuterated products also prolonged prothrombin time (PT),...