Spinal antinociceptive effects of AA501, a novel chimeric peptide with opioid receptor agonist and tachykinin receptor antagonist moieties.
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.
Bonney
Iwona Maszczynska
IM
Department of Anesthesia, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA. IBonney@tufts-nemc.org
Foran
Stacy E
SE
Marchand
James E
JE
Lipkowski
Andrzej W
AW
Carr
Daniel B
DB
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
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