Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure

Huang, Guozheng; Pemp, Daniela; Stadtmüller, Patricia; Nimczick, Martin; Heilmann, Jörg; Decker, Michael

doi:10.1016/j.bmcl.2014.07.038

Cited by 19 publications

(28 citation statements)

References 38 publications

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“…44-45 Bivalent ligands offer a potential avenue to target melanocortin GPCR dimers and investigate their functional effects both in vitro and in vivo . Since Portoghese and coworkers pioneered bivalent ligands targeting GPCRs, 46 bivalent ligands have been developed for various GPCR systems including the opioid, 46-50 serotonin, 51-53 adenosine, 54 cannabinoid, 55-56 chemokine, 57 dopamine, 58 and melanocortin receptors. 25, 59-69 Bivalent ligands have been demonstrated to have a variety of different pharmacological effects as compared to their monovalent counterparts including: increasing or decreasing binding affinity, 52, 58, 64 positively or negatively changing functional responses, 53-55, 59, 70 altering receptor subtype selectivity, 47, 58 changing receptor trafficking, 71-73 and creating tissue selectivity.…”

Section: Introductionmentioning

confidence: 99%

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

et al. 2016

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Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 (CJL-1-140) possessed a functional profile that was unique from its monovalent counterparts providing evidence of the discrete effects of bivalent ligands. Lead compound 7 (CJL-1-87) significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects.

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Section: Introductionmentioning

confidence: 99%

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

et al. 2016

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“…Bivalent ligand design strategies have been utilized to develop novel ligands for various GPCR systems including the opioids, 1–8 gonadotropin-releasing hormone receptor, 9, 10 adenosine, 11 cannabinoid, 12, 13 serotonin, 14–16 dopamine, 17, 18 chemokine, 6, 19 oxytocin, 20 and melanocortin receptor systems. 21–36 There has been increasing evidence that heterobivalent ligands featuring pharmacophores for two different receptors can be an efficacious targeting strategy for heterodimers and results in unique properties in vivo .…”

Section: Introductionmentioning

confidence: 99%

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

Lensing

Adank

Wilber

et al. 2017

ACS Chem. Neurosci.

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Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro, however studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH2 on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an anti-obesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2 to 8 hours after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 hours after administration (p < 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T1/2 = 6.0 h and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand’s unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease in vivo food intake, decrease mice’s body fat percent, and differentially affect mouse hormone levels demonstrates the distinct characteristics achieved from the current melanocortin agonist bivalent design strategy.

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“…The anticancer activity of UA has also been reported in different types of cancer cell lines ( 10 – 12 ). UA is therefore an effective anticancer agent to which extensive structural changes have been made in order to further increase its anticancer activity ( 32 ). Several studies have reported that modified derivatives of UA with functional groups at the C-3 and/or C-28 positions exhibit significant bioactivity ( 33 – 35 ).…”

Section: Discussionmentioning

confidence: 99%

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

Zhang

Nie

et al. 2017

Oncol Lett

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The present study investigated the anticancer functions of ursolic acid (UA) and its novel derivatives, with a nitrogen-containing heterocyclic scaffold and the privileged fragment at the C-28 position on apoptosis induction, cell proliferation and cell cycle in human BC lines. UA was chemically modified in the present study to increase its antitumor activity and bioavailability. A novel UA derivative, FZU3010, was synthesized using a nitrogen-containing heterocyclic scaffold and a privileged fragment at the C-28 position. Sulforhodimine B assays were used to measure the effect of UA and different concentrations of FZU3010 on the viability of breast cancer (BC) SUM149PT and HCC1937 cells. FZU3010 significantly repressed the proliferation of the two cancer cell lines in a dose-dependent manner, with a half-maximal inhibitory concentration of 4–6 µM, and exhibited decreased cytotoxicity compared with vehicle-treated cell lines. The effect of FZU3010 on cell cycle distribution and cellular apoptosis was also investigated. The results of this investigation indicated that FZU3010 significantly increased the number of SUM149PT and breast cancer HCC1937 cells in the G0/G1 phase in a dose-dependent manner. Additionally, at a concentration of 5 µM, the capability of FZU3010 to induce BC apoptosis was significantly higher than the capability of UA. Thus, the results of the current study indicated that FZU3010 induced apoptosis in BC cells, together with induction of cell cycle arrest at the S and G0/G1 phase. FZU3010 may therefore be considered as a potential therapeutic agent for the treatment of BC.

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Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure

Cited by 19 publications

References 38 publications

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

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Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure

Cited by 19 publications

References 38 publications

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines

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A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage