Evidence map›Paper›PMID 25411367›Full record

ArticleMolecular pharmacology2015

(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.

Mariam M Mahmoud, Teresa Olszewska, Hui Liu, Derek M Shore, Dow P Hurst, Patricia H Reggio, Dai Lu, Debra A Kendall

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.6field-weighted citation impact, top 27% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 3 citations in OpenAlex.

  1. Discovery of Selective Cannabinoid CBSLAS discovery : advancing life sciences R & D · 2018
    Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

Mariam M MahmoudDepartment 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.).
Teresa OlszewskaDepartment 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.).
Hui LiuDepartment 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.).
Derek M ShoreDepartment 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.).
Dow P HurstDepartment 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.).
Patricia H ReggioDepartment 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.).
Dai LuDepartment 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 A KendallDepartment 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.
University of North Carolina at Greensboro · USTexas A&M Health Science Center · USUniversity of Connecticut · US

Funding

Molecular Determinants of Cannabinoid ActivityR01DA003934 · NIDA · UNIVERSITY OF NORTH CAROLINA GREENSBORO · PI REGGIO, PATRICIA HODAPP · 1985 to 2019
$5.6M
Determinants of the Cannabinoid Receptor Life CycleR01DA020763 · NIDA · UNIVERSITY OF CONNECTICUT STORRS · PI KENDALL, DEBRA A · 2007 to 2011
$1.5M
Senior Scientist Award: Molecular Determinants for Cannabinoid ActivityK05DA021358 · NIDA · UNIVERSITY OF NORTH CAROLINA GREENSBORO · PI REGGIO, PATRICIA HODAPP · 2007 to 2016
$1.3M
NIDA NIH HHS K05 DA021358NIDA NIH HHS K05-DA021358NIDA NIH HHS R01 DA003934NIDA NIH HHS R01-DA003934NIDA NIH HHS R01 DA020763NIDA NIH HHS R01-DA020763
6 · The paper itself

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.

Indexed as

Drug Inverse AgonismAnimalsBenzhydryl CompoundsCannabinoidsCattleHEK293 CellsHumansPiperazinePiperazinesProtein BindingProtein Structure, SecondaryReceptor, Cannabinoid, CB1Benzhydryl CompoundsCannabinoidsPiperazinePiperazinesReceptor, Cannabinoid, CB1

Identifiers

PMID25411367
PMCPMC4293445
OpenAlexW2335638235

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.