William E FANTEGROSSI,Aaron JANOWSKY,Amy J ESHLEMAN,Lauren N RUSSELL,Saki FUKUDA,Jyoti GOGOI,Cassandra PRIOLEAU,Ambuja S BALE,Srihari R TELLA,Merle GPAULE,2,Takato HIRANITA,2

(1.Department of Pharmacology and Toxicology,College of Medicine,University of Arkansas for Medical Sciences,AR 72207;2.Division of Neurotoxicology,National Center for Toxicological Research,Food and Drug Administration,AR 72079;3.Departments of Psychiatry and Behavioral Neuroscience,Oregon Health&Science University,Portland,OR 97239-3098;4.VA Portland Health Care System,Portland,OR 97239;5.Drug and Chemical Evaluation Section,Drug Enforcement Administration)

T3-4

Pharmacological characterizationof synthetic cannabinoid MAM-2201:radioligand binding and abuse-related effects

William E FANTEGROSSI1,Aaron JANOWSKY3,4,Amy J ESHLEMAN3,4,Lauren N RUSSELL1,Saki FUKUDA1,Jyoti GOGOI1,Cassandra PRIOLEAU5,Ambuja S BALE5,Srihari R TELLA5,Merle GPAULE1,2,Takato HIRANITA1,2

(1.Department of Pharmacology and Toxicology,College of Medicine,University of Arkansas for Medical Sciences,AR 72207;2.Division of Neurotoxicology,National Center for Toxicological Research,Food and Drug Administration,AR 72079;3.Departments of Psychiatry and Behavioral Neuroscience,Oregon Health&Science University,Portland,OR 97239-3098;4.VA Portland Health Care System,Portland,OR 97239;5.Drug and Chemical Evaluation Section,Drug Enforcement Administration)

OBJECTIVEOver 30%of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a ″graymarket″drug of abuse bystruc?turally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODSThe present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1Rs])and in vivo(in mice and rats).RESULTSIn a radioligand binding assay using[3H]CP55,940 in HEK cell membranes transfected with the CB1R,MAM-2201(Ki=5.4 nmol·L-1),had higher binding affinity than WIN 55,212-2(Ki=80 nmol·L-1),and D9-THC(Ki=8.3 nmol·L-1).The Emaxvalues for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated cAMP were 85%(EC50=0.45 nmol·L-1)and 95%,respectively,as compared with the D9-THC Emaxof 74%.In mice,MAM-2201(0.003-1.0 mg·kg-1,IP)produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg-1,analgesia:ED50=0.125 and 29.4 mg·kg-1,and catalepsy:ED50=0.301 and 18.9 mg·kg-1in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg-1in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like intero?ceptive effects in subjects trained to discriminate 3.0 mg·kg-1(IP)D9-THC from saline.CONCLUSIONMAM-2201 binds CB1Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.

cannabinoid;CB1 receptor;behavior;abuse liability

The project supported by Drug Enforcement Administration,National Center for Toxicological Research(protocol#E0763601)and University of Arkansas for Medical Sciences

William E FANTEGROSSI,Tel:15016868645,E-mail:WEFantegrossi@uams.edu