title: Nonpeptide small molecule agonist and antagonist original leads for neuropeptide FF1 and FF2 receptors.
abstract: Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance, and dependence. Currently, no small molecules displaying good affinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first nonpeptide small molecule scaffold for NPFF1,2-R, the guanidino-piperidines, and SAR studies resulting in the discovery of a NPFF1 agonist (7b, K(i) = 487 ± 117 nM), a NPFF1 antagonist (46, K(i) = 81 ± 17 nM), and a NPFF2 partial antagonist (53a, K(i) = 30 ± 5 nM), which serve as leads for the development of pharmacological probes and potential therapeutic agents. Testing of 46 alone was without effect in the mouse 48 °C warm-water tail-withdrawal test, but pretreatment with 46 prevented NPFF-induced hyperalgesia.
authors.affiliation: Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi , University, Mississippi 38677, United States.
authors.forename: V Blair
authors.initials: VB
authors.lastname: Journigan
authors.forename: Christophe
authors.initials: C
authors.lastname: Mésangeau
authors.forename: Neha
authors.initials: N
authors.lastname: Vyas
authors.forename: Shainnel O
authors.initials: SO
authors.lastname: Eans
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006146:Guanidines / Q000138:chemical synthesis* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000595648:1-benzyl-N-(2-guanidinoethyl)-4-(phenylamino)piperidine-4-carboxamide; C000595647:2-amino-N-((1-benzyl-4-(phenylamino)piperidin-4-yl)methyl)-5-guanidinopentanamide; D006146:Guanidines; D008024:Ligands; C000595649:N-((1-benzyl-4-(naphthalen-1-ylmethyl)piperidin-4-yl)methyl)-2-guanidinoacetamide; D009281:Naphthalenes; D010880:Piperidines; D018013:Receptors, Neuropeptide; D011957:Receptors, Opioid; C083929:neuropeptide FF receptor