title: New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus.
abstract: The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Group Research Ltd., Ware, Hertfordshire, England.
authors.forename: D I
authors.initials: DI
authors.lastname: Scopes
authors.forename: N F
authors.initials: NF
authors.lastname: Hayes
authors.forename: D E
authors.initials: DE
authors.lastname: Bays
authors.forename: D
authors.initials: D
authors.lastname: Belton
authors.forename: J
authors.initials: J
authors.lastname: Brain
authors.forename: D S
authors.initials: DS
authors.lastname: Brown
authors.forename: D B
authors.initials: DB
authors.lastname: Judd
authors.forename: A B
authors.initials: AB
authors.lastname: McElroy
authors.forename: C A
authors.initials: CA
authors.lastname: Meerholz
authors.forename: A
authors.initials: A
authors.lastname: Naylor
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa