title: Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis.
abstract: We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB1Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism.
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Malliga R
authors.identifier: 0000-0002-0116-4619
authors.initials: MR
authors.lastname: Iyer
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Alexis
authors.initials: A
authors.lastname: Katz
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gao
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Coffey
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Laboratory of Physiologic Studies, and ‡Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Rockville, Maryland 20852, United States.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D052247:Nitric Oxide Synthase Type II