Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog.
OBJECTIVE
To characterize in vivo the high-affinity CB(1) cannabinoid receptor (CB(1)R) selective anandamide analog AM1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination. Substitution tests involved Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of anandamide (AEA), as well as the CB(1)R antagonist/inverse agonist rimonabant; D: -amphetamine and morphine were also examined to assess pharmacological specificity.


METHODS
Rats were initially trained to discriminate between i.p.-injected vehicle and 3 mg/kg AM1346 (group 3 mg/kg; t' = 20 min); subsequently, the rats were retrained with 5.6 mg/kg AM1346 (group 5.6 mg/kg; t' = 20 min).


RESULTS
Dose-generalization curves of AM1346, Delta(9)-THC, and mAEA suggested the following order of potency: Delta(9)-THC > AM1346 > mAEA both for rats discriminating between 3 and 5.6 mg/kg AM1346 from vehicle. In group 3 mg/kg, challenge by 1 mg/kg rimonabant resulted in parallel shifts to the right of the dose-generalization curves for Delta(9)-THC and AM1346, suggesting surmountable antagonism. Surmountable antagonism was not demonstrated with rimonabant-mAEA combinations. A long duration of effect was indicated when 3 mg/kg AM1346 was examined after different time intervals following i.p. administration (group 3 mg/kg). The in vivo half-life was close to 5 h. Neither D: -amphetamine nor morphine generalized in either of groups 3 mg/kg and 5.6 mg/kg, suggesting pharmacological specificity.


CONCLUSIONS
Unlike mAEA, the surmountable antagonism between rimonabant and AM1346 showed that the structural features of AEA can be modified to produce novel ligands that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB(1)R agonists derived from an AEA template.
Järbe
Torbjörn U C
TU
Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA 19122, USA. t.jarbe@neu.edu
Li
Chen
C
Liu
Qian
Q
Makriyannis
Alexandros
A
D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013329:Structure-Activity Relationship
C517735:AM-1346; D001095:Arachidonic Acids; D063388:Endocannabinoids; D008024:Ligands; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C088155:methanandamide; D013759:Dronabinol; D000077285:Rimonabant; C078814:anandamide