piperidines and vasicine

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.

Topics: Alkaloids; Aminopyridines; Animals; Antihypertensive Agents; Biological Products; Blood Pressure; Dose-Response Relationship, Drug; Female; Hypertension; Injections, Intravenous; Mice; Molecular Structure; Piperidines; Quinazolines; Rats; Rats, Wistar; Structure-Activity Relationship

Experiments were conducted to evaluate the scientific basis of the use of the trikatu group of acrids (long pepper, black pepper and ginger) in the large number of prescriptions in Ayurveda. [3H] vasicine and [3H] sparteine were taken as test drugs. Piper longum (long pepper) increased the blood levels of vasicine by nearly 233%. Under the influence of piperine, the active principle of Piper species, sparteine blood levels increased more than 100%. The results suggest that these acrids have the capacity to increase the bioavailability of certain drugs. It appears that the trikatu group of drugs increase bioavailability either by promoting rapid absorption from the gastrointestinal tract, or by protecting the drug from being metabolised/oxidised in its first passage through the liver after being absorbed, or by a combination of these two mechanisms.

Topics: Abortifacient Agents; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Synergism; Female; India; Medicine, Ayurvedic; Pharmaceutical Preparations; Phytotherapy; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Quinazolines; Rats; Sparteine