Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes
Giardina, G.; Clarke, G.D.; Grugni, M.; Sbacchi, M.; Vecchietti, V.
Farmaco 50(6): 405-418
1995
ISSN/ISBN: 0014-827X PMID: 7669179 Document Number: 453401
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.