title: Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.
abstract: This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.
authors.affiliation: SmithKline Beecham Farmaceutici S.p.A., Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: G
authors.initials: G
authors.lastname: Dondio
authors.forename: G
authors.initials: G
authors.lastname: Petrone
authors.forename: M
authors.initials: M
authors.lastname: Sbacchi
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D004231:Diuresis / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011759:Pyrrolidines; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D044024:Tetralones
chemical_list: C090022:2-((dimethylamino)methyl)-1-((5,6,7,8-tetrahydro-5-oxo-2-naphthyl)acetyl)piperidine; D000700:Analgesics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013764:Tetrahydronaphthalenes; D044024:Tetralones; C051272:spiradoline