Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.
New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.
Holladay
M W
MW
Neurological and Urological Diseases Research D-47W, Abbott Laboratory, Abbott Park, Illinois 60064-3500, USA. mark.w.holladay@abbott.com
Wasicak
J T
JT
Lin
N H
NH
He
Y
Y
Ryther
K B
KB
Bannon
A W
AW
Buckley
M J
MJ
Kim
D J
DJ
Decker
M W
MW
Anderson
D J
DJ
Campbell
J E
JE
Kuntzweiler
T A
TA
Donnelly-Roberts
D L
DL
Piattoni-Kaplan
M
M
Briggs
C A
CA
Williams
M
M
Arneric
S P
SP
D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000502:physiology; D010146:Pain; D010147:Pain Measurement; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014981:Xenopus
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018712:Analgesics, Non-Narcotic; D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins