A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents.
OBJECTIVE
Cannabinoid CB(1) receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.


METHODS
Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated.


RESULTS
AM6545 binds to CB(1) receptors with a K(i) of 1.7 nM and CB(2) receptors with a K(i) of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB(1) receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB(1) receptor gene-deficient mice, but not in CB(1)/CB(2) receptor double knockout mice.


CONCLUSIONS
Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
Cluny
N L
NL
Department of Physiology & Pharmacology, Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, AB, Canada.
Vemuri
V K
VK
Chambers
A P
AP
Limebeer
C L
CL
Bedard
H
H
Wood
J T
JT
Lutz
B
B
Zimmer
A
A
Parker
L A
LA
Makriyannis
A
A
Sharkey
K A
KA
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D048588:Benzoxazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism
C529765:AM4113; C551825:AM6545; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000242:Cyclic AMP