Synthesis and antinociceptive activity of pyrrolidinylnaphthalenes.
In this paper the synthesis of the racemates (2R,3S/2S,3R)-1,2-dimethyl-3-[2-(6-substituted naphthyl)]-3-hydroxypyrrolidine 1b-d [(2R,3S/2S,3R)-1b-d] are reported. Compounds 1b-d were prepared by reaction of the racemic 1,2-dimethyl-3-pyrrolidone 2 with the lithiation product obtained from 2-bromo-6-substituted naphthalene 3b-d. Pharmacological properties of (2R,3S/2S,3R)-1a-d are also described. Analgesic activity was investigated by the hot plate test and binding affinities towards mu, delta and kappa opioid receptors were evaluated. A preliminary evaluation of the in vivo side-effects was also accomplished using the rota-rod test. Interesting antinociceptive activity was shown by all compounds and in particular by 1d, which is the most active compound, since it is six-fold more potent than morphine and has lower side effects on the locomotory activity.
Collina
S
S
Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy. collina@chifar.unipv.it
Azzolina
O
O
Vercesi
D
D
Sbacchi
M
M
Scheideler
M A
MA
Barbieri
A
A
Lanza
E
E
Ghislandi
V
V
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000700:Analgesics; D009281:Naphthalenes; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; C055382:naltrindole