title: Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2.
abstract: The potential clinical utility of galanin peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia. In addition to possessing potent anticonvulsant efficacy, galanin analogs are analgesic in various assays. The purpose of these studies was to evaluate the lead galanin receptor type 2 (GalR2)-preferring analog, NAX 810-2, in various pain assays, as well as determine any potential for insulin inhibition, growth hormone stimulation, and cognitive impairment. NAX 810-2 was evaluated in mouse (carrageenan, formalin, tail flick, plantar incision) and rat pain models (partial sciatic nerve ligation). NAX 810-2 dose-dependently increased paw withdrawal latency following plantar administration of carrageenan (ED504.7 mg/kg). At a dose of 8 mg/kg, NAX 810-2 significantly attenuated nociceptive behaviors following plantar administration of formalin, and this was observed for both phase I (acute) and phase II (inflammatory) components of the formalin behavioral response. NAX-810-2 was active at higher doses in the mouse tail flick model (ED5020.2 mg/kg) and similarly, reduced mechanical allodynia following plantar incision in mice at a dose of 24 mg/kg. NAX 810-2 also reduced mechanical allodynia in the partial sciatic nerve ligation model at a dose of 4 mg/kg. In addition, NAX 810-2 did not impair insulin secretion at doses of 2.5 and 8 mg/kg (acutely) or at a dose of 8 mg/kg given daily for 5 days. Similarly, 8 mg/kg (twice daily, 5 days) of NAX 810-2 did not increase growth hormone levels. These results demonstrate that NAX 810-2 possesses a favorable pre-clinical profile as a novel and first-in-class analgesic.
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Room 201, Salt Lake City, UT, 84112, USA. cameron.s.metcalf@utah.edu.|NeuroAdjuvants, Inc., Salt Lake City, UT, USA. cameron.s.metcalf@utah.edu.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Metcalf
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Room 201, Salt Lake City, UT, 84112, USA.|School of Dentistry, University of Utah, Salt Lake City, UT, USA.
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Room 201, Salt Lake City, UT, 84112, USA.|NeuroAdjuvants, Inc., Salt Lake City, UT, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.affiliation: NeuroAdjuvants, Inc., Salt Lake City, UT, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McDougle
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019004:Galanin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism*
chemical_list: D000700:Analgesics; C000620868:NAX 810-2; D044092:Receptor, Galanin, Type 2; D019004:Galanin
keywords: Analgesic; Drug development; Galanin; Neuropeptide; Pain; Toxicology