title: Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes.
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.
authors.affiliation: Department of Chemistry, SmithKline Beecham Farmaceutici s.p.a., Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: M
authors.initials: M
authors.lastname: Grugni
authors.forename: M
authors.initials: M
authors.lastname: Sbacchi
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects*; D006801:Humans; D007928:Lethal Dose 50; D017933:Peripheral Nervous System / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000700:Analgesics; D017473:Receptors, Opioid, kappa