Synthesis, Metabolism, Structure Modification Of Perlolyrine And Pharmacological Study Of Perlolyrine Analogues

OBJECTIVE: The traditional Chinese herb, Chuanxiong (Ligusticum Wallichii Franch) is prescribed to promote blood circulation and relieve hemostasis. It 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. Perlolyrine, 1-(5-hydroxymethyl-2-furyl)-9H-pyrido[3,4-b]indole, an active ingredient from Chuanxiong, has also been used in the treatment of coronary atherosclerotic heart disease and cerebrovascular diseases after confirmation of its potency by preliminary pharmacological experiments. However, it has been reported that perlolyrine metabolizes too rapidly, its bioavailability is too low and its effects disappear too fast. So it is necessary to study the structure — activiyy relationship (SAR) of perlolyrine and to modify its chemical structure, in order to develop new drug with high potency, rapid effect, low toxicity and low price. METHODS: 1. Perlolyrine was synthesized by two schemes: one scheme being the reaction of 5-acetoxymethyl-2-formylfuran and tryptophan, the other scheme being the reaction of 5-acetoxymethyl-2-formylfuran and tryptamine. In order to prepare [2-¹⁵N]perlolyrine and deuterium labelled perlolyrine, two methods of synthesizing [ α-¹⁵N] tryptophan and deuterium labelled tryptophan were designed. 2. The urine was collected after i. g. (gastric injection) administration of either perlolyrine or [2-¹⁵N]perlolyrine or deuterium labelled perlolyrine to male Wistar rats at the dose of 250mg/kg in 24 hours. The metabolites were extracted with carbonate — organic solvent. The nonacidic (neutral and basic) fractions derivatized with MSTFA were subjected to GC-MS for analysis and the water...