title: Antipruritic and antihyperalgesic actions of loperamide and analogs.
abstract: Loperamide and three of its analogs were evaluated for their ability to inhibit binding to cloned human opioid receptor subtypes and to produce antipruritus and antinociception following local s.c. administration to rodents. All four compounds were fully efficacious agonists with affinities of 2 to 4 nM for the cloned human mu opioid receptor. Local s.c. injection of loperamide, ADL 01-0001 or ADL 01-0002 at the same site as the introduction of the pruritogenic compound 48/80 resulted in antipruritic activity in a mouse model of itch. Similarly, i.paw or i.pl. administration of compounds ADL 01-0001, ADL 01-0002 and ADL 01-0003 to inflamed paws caused potent antinociception, inhibiting late phase formalin-induced flinching, Freund's adjuvant-induced mechanical hyperalgesia and tape stripping-induced mechanical hyperalgesia. Loperamide and its analogs were efficacious in animal models of itch and inflammatory pain, and may have potential therapeutic utility as antipruritic and antihyperalgesic agents.
authors.affiliation: Department of Pharmacology, Adolor Corporation, 371 Phoenixville Pike, Malvern, PA 19355, USA. ddehavenhudkins@adolor.com
authors.forename: Diane L
authors.initials: DL
authors.lastname: DeHaven-Hudkins
authors.forename: Alan
authors.initials: A
authors.lastname: Cowan
authors.forename: Luz
authors.initials: L
authors.lastname: Cortes Burgos
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Daubert
authors.forename: Joel A
authors.initials: JA
authors.lastname: Cassel
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: George B
authors.initials: GB
authors.lastname: Kehner
authors.forename: Virendra
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000982:Antipruritics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008139:Loperamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D000700:Analgesics; D000982:Antipruritics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D008139:Loperamide