title: Spinal antinociceptive effects of AA501, a novel chimeric peptide with opioid receptor agonist and tachykinin receptor antagonist moieties.
abstract: The use of "multimodal" combination analgesic therapies or novel single molecules possessing multiple analgesic targets is becoming increasingly attractive. In previous experiments we showed that a substance P antagonist injected intrathecally potentiated the antinociceptive effects of potent opioid receptor agonist, biphalin. Based on examination of the biphalin structure-activity relationship, we designed and synthesized a novel chimeric peptide, termed AA501 (N'(Tyr-D-Ala-Gly-Phe), N"(Z-Trp) hydrazide, Z=benzyloxycarbonyl). AA501 consists of an opioid receptor agonist pharmacophore related to biphalin and a substance P receptor antagonist pharmacophore, both linked by a hydrazide bridge. The present study evaluates the ability of a novel chimeric peptide, AA501, to bind to opioid and substance P receptors and to produce antinociception in tail-flick and formalin tests, and in a neuropathic pain model when administered intrathecally to rats.
authors.affiliation: Department of Anesthesia, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA. IBonney@tufts-nemc.org
authors.forename: Iwona Maszczynska
authors.initials: IM
authors.lastname: Bonney
authors.forename: Stacy E
authors.initials: SE
authors.lastname: Foran
authors.forename: James E
authors.initials: JE
authors.lastname: Marchand
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Carr
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002404:Catheterization; D004361:Drug Tolerance; D005557:Formaldehyde; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
chemical_list: C493307:AA501 peptide; D000700:Analgesics; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D018039:Receptors, Tachykinin; D011993:Recombinant Fusion Proteins; D005557:Formaldehyde