title: Combinatorial lead optimization of a neuropeptide FF antagonist.
abstract: The tripeptide Pro-Gln-Arg-NH2, derivatized at the secondary amino group of the proline residue with 5-(dimethylamino)-1-naphthalenesulfonyl (dansyl-PQR-NH2), antagonizes the central anti-opioid action of neuropeptide FF in animals after systemic administration and, therefore, is a therapeutic lead to treat opiate withdrawal. For a combinatorial optimization to improve potency, libraries focused on the possible replacement of the proline and glutamine residues of this lead compound were obtained by a solid-phase split-and-mix method using coded amino acids (excluding cysteine) as building blocks. After screening for competitive binding against a radioiodinated neuropeptide FF analogue, 5-(dimethylamino)-1-naphthalenesulfonyl-Gly-Ser-Arg-NH2 (dansyl-GSR-NH2) has emerged as one of the compounds in the library with high affinity to the NPFF receptor and even with a moderate increase compared to dansyl-PQR-NH2 in its predicted ability to penetrate the central nervous system.
authors.affiliation: Center for Drug Discovery, College of Pharmacy, and The McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. lprokai@grove.ufl.edu
authors.forename: L
authors.initials: L
authors.lastname: Prokai
authors.forename: K
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.forename: A
authors.initials: A
authors.lastname: Zharikova
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: J R
authors.initials: JR
authors.lastname: Rocca
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D003619:Dansyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018013:Receptors, Neuropeptide / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C427233:5-(dimethylamino)-1-naphthalenesulfonyl-glycyl-seryl-argininamide; D003619:Dansyl Compounds; D009842:Oligopeptides; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide