Arizona Health Sciences

Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain.

TitleNovel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain.
Publication TypeJournal Article
Year of Publication2011
AuthorsHanlon KE, Herman DS, Agnes RS, Largent-Milnes TM, Kumarasinghe IR, Ma SW, Guo W, Lee Y-S, Ossipov MH, Hruby VJ, Lai J, Porreca F, Vanderah TW
JournalBrain Res
Volume1395
Pagination1-11
Date Published2011 Jun 13
ISSN1872-6240
KeywordsAnalgesics, Opioid, Animals, Disease Models, Animal, Drug Design, Male, Neuralgia, Neuropeptides, Oligopeptides, Peripheral Nervous System Diseases, Rats, Rats, Sprague-Dawley, Receptor, Cholecystokinin A, Receptor, Cholecystokinin B, Receptors, Neuropeptide, Receptors, Opioid, delta, Receptors, Opioid, mu
Abstract

The conventional design of high affinity drugs targeted to a single molecule has not resulted in clinically useful therapies for pain relief. Recent reviews have suggested that newly designed analgesic drugs should incorporate multiple targets. The distributions of cholecystokinin (CCK) and CCK receptors in the central nervous system (CNS) overlap significantly with endogenous opioid systems and can be dually targeted. CCK has been shown to act as an endogenous "anti-analgesic" peptide and neuropathic pain conditions promote endogenous CCK release in CNS regions of pain modulation. Administration of CCK into nuclei of the rostral ventromedial medulla induces pronociceptive behaviors in rats. RSA 504 and RSA 601 are novel bifunctional compounds developed to target neuropathic pain by simultaneously acting as agonists at two distinct opioid receptors and antagonizing CCK receptors in the CNS. RSA 504 and RSA 601 demonstrate agonist activity in vitro and antihypersensitivity to mechanical and thermal stimuli in vivo using the spinal nerve ligation model of neuropathic pain. Intrathecal administration of RSA 504 and RSA 601 did not demonstrate antinociceptive tolerance over 7 days of administration and did not display motor impairment or sedation using a rotarod. These are the first behavioral studies that demonstrate how multi-targeted molecule design can address the pathology of neuropathic pain. These compounds with δ and μ opioid agonist activity and CCK antagonist activity within one molecule offer a novel approach with efficacy for neuropathic pain while lacking the side effects typically caused by conventional opioid therapies.

DOI10.1016/j.brainres.2011.04.024
Alternate JournalBrain Res.
PubMed ID21550594
PubMed Central IDPMC3105124
Grant ListR01 DA015205-05 / DA / NIDA NIH HHS / United States
R01 DA015205 / DA / NIDA NIH HHS / United States
2P01DA006284.1 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
K02 DA018717-05 / DA / NIDA NIH HHS / United States
K02 DA018717 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Frank Porreca, Ph.D.
Todd Vanderah, Ph.D.