Discovery of selective nonpeptidergic neuropeptide FF2 receptor agonists.
We report the discovery and initial characterization of a novel class of selective NPFF2 agonists. HTS screening using R-SAT, a whole cell based functional assay, identified a class of aryliminoguanidines as NPFF1 and NPFF2 ligands. Subsequent optimization led to molecules exhibiting selective NPFF2 agonistic activity. Systemic administration showed that selective NPFF2 agonists (1 and 3) are active in various pain models in vivo, whereas administration of a nonselective NPFF1 and NPFF2 agonist (9) increases sensitivity to noxious and non-noxious stimuli.
Gaubert
Gilles
G
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden.
Bertozzi
Fabio
F
Kelly
Nicholas M
NM
Pawlas
Jan
J
Scully
Audra L
AL
Nash
Norman R
NR
Gardell
Luis R
LR
Lameh
Jelveh
J
Olsson
Roger
R
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000037:antagonists & inhibitors
D000700:Analgesics; D006146:Guanidines; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D002351:Carrageenan