title: Preclinical evaluation of intravenous NAX 810-2, a novel GalR2-preferring analog, for anticonvulsant efficacy and pharmacokinetics.
abstract: Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice.
  
  
  
  NAX 810-2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF-1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810-2 levels were determined from trunk blood samples. NAX 810-2 was also added to human plasma at various concentrations for determination of plasma protein binding.
  
  
  
  In the mouse corneal kindling model, NAX 810-2 dose-dependently blocked seizures following intravenous administration (median effective dose [ED50], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810-2 dose-dependently blocked seizures following bolus administration (0.375-1.5 mg/kg, i.v.; ED50, 0.7 mg/kg), with a time-to-peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one-half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810-2 show linear pharmacokinetics following intravenous administration and a half-life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810-2 effectively activates GalR2 at therapeutic concentrations.
  
  
  
  These studies further suggest the potential utility of NAX 810-2 as a novel therapy for epilepsy.
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, U.S.A.|NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Metcalf
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, U.S.A.|NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.affiliation: NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.
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, Utah, U.S.A.
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Utah Health Sciences Center, Salt Lake City, Utah, U.S.A.
authors.forename: Dan
authors.initials: D
authors.lastname: Kaufmann
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, U.S.A.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D003315:Cornea / Q000294:innervation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation / Q000009:adverse effects; D019004:Galanin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D007275:Injections, Intravenous; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D011485:Protein Binding / Q000187:drug effects; D044091:Receptor, Galanin, Type 1 / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012640:Seizures / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; C000620868:NAX 810-2; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D019004:Galanin
keywords: Antiseizure drug; Blood-brain barrier; Drug discovery; Epilepsy; Galanin; Neuropeptide; Pharmacokinetic; Seizure