title: (4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229): a new cannabinoid CB1 receptor inverse agonist from the class of benzhydryl piperazine analogs.
abstract: Some inverse agonists of cannabinoid receptor type 1 (CB1) have been demonstrated to be anorectic antiobesity drug candidates. However, the first generation of CB1 inverse agonists, represented by rimonabant (SR141716A), otenabant, and taranabant, are centrally active, with a high level of psychiatric side effects. Hence, the discovery of CB1 inverse agonists with a chemical scaffold distinct from these holds promise for developing peripherally active CB1 inverse agonists with fewer side effects. We generated a new CB1 inverse agonist, (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229), from the class of benzhydryl piperazine analogs. This compound binds to CB1 more selectively than cannabinoid receptor type 2, with a Ki value of 220 nM. Comparable CB1 binding was also observed by analogs 1-[bis(4-fluorophenyl)methyl]-4-cinnamylpiperazine dihydrochloride (LDK1203) and 1-[bis(4-fluorophenyl)methyl]-4-tosylpiperazine hydrochloride (LDK1222), which differed by the substitution on the piperazine ring where the piperazine of LDK1203 and LDK1222 are substituted by an alkyl group and a tosyl group, respectively. LDK1229 exhibits efficacy comparable with SR141716A in antagonizing the basal G protein coupling activity of CB1, as indicated by a reduction in guanosine 5'-O-(3-thio)triphosphate binding. Consistent with inverse agonist behavior, increased cell surface localization of CB1 upon treatment with LDK1229 was also observed. Although docking and mutational analysis showed that LDK1229 forms similar interactions with the receptor as SR141716A does, the benzhydryl piperazine scaffold is structurally distinct from the first-generation CB1 inverse agonists. It offers new opportunities for developing novel CB1 inverse agonists through the optimization of molecular properties, such as the polar surface area and hydrophilicity, to reduce the central activity observed with SR141716A.
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Mariam M
authors.initials: MM
authors.lastname: Mahmoud
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Teresa
authors.initials: T
authors.lastname: Olszewska
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Derek M
authors.initials: DM
authors.lastname: Shore
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.).
authors.forename: Dai
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut (M.M.M.); Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas (T.O., H. L., D.L.); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (D.M.S., D.P.H., P.H.R.); and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.A.K.) debra.kendall@uconn.edu.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kendall
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D002186:Cannabinoids; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D000077489:Piperazine