1. Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes.
- Author
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Giardina G, Clarke GD, Grugni M, Sbacchi M, and Vecchietti V
- Subjects
- Analgesics pharmacokinetics, Analgesics pharmacology, Animals, Humans, Lethal Dose 50, Analgesics chemical synthesis, Blood-Brain Barrier drug effects, Central Nervous System drug effects, Peripheral Nervous System drug effects, Receptors, Opioid, kappa agonists
- Abstract
Over the past decade there has been great interest by the pharmaceutical industry in the development of novel analgesics which act by activation of central kappa-opioid receptors. However, in view of the spectrum of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ability to cross the blood-brain barrier (BBB). In this review, the authors consider the chemical strategies and associated synthetic procedures employed by various research groups to produce hydrophilic compounds with retained kappa-opioid agonist activity. Physico-chemical (clogP, delta logP) and biological methods (antinociception following administration by peripheral and central routes; ex-vivo binding to detect plasma and brain levels of the drugs) utilized to assess brain penetration are described and compared. Overall, in-vivo ratios correlate better with delta logP values than with clogP.
- Published
- 1995