MCOPPB trihydrochloride

MCOPPB trihydrochloride is a potent and non-peptide agonist of Nociceptin/Orphanin FQ (NOP) receptor with EC50 value of 0.39nM [1].

NOP receptor is an opioid-receptor-like-1 receptor and its ligand is nociceptin. They locate in forebrain and take part in the integration of the emotional components of fear and stress. As the most potent full agonist of NOP receptor, MCOPPB is developed as an anxiolytic. The Ki value of MCOPPB for the binding affinity to recombinant human NOP receptor is 0.085nM. The EC50 value of MCOPPB is 0.39nM in HEK293 cells through testing the binding of radiolabeled ligand to G-protein induced by the binding of MCOPPB to hNOP receptor. In addition, MCOPPB is more selective to NOP receptor over other opioid receptors including µ, κ, and δ. The Ki values of MCOPPB for these opioid receptors are more than 10 fold bigger than for hNOP receptor [1].

References:
[1] Hayashi S, Hirao A, Imai A, et al. Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3 R)-3-piperidinyl]-1 H-benzimidazole: Design, Synthesis, and Structure- Activity Relationship of Oral Receptor Occupancy in the Brain for Orally Potent Antianxiety Drug (1, 2). Journal of medicinal chemistry, 2009, 52(3): 610-625.

Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma.[Pubmed:17454628]

Leuk Lymphoma. 2007 Apr;48(4):708-15.

A phase I/II trial was performed to investigate the safety and tolerance of zosuquidar.3HCL, a potent inhibitor of P-glycoprotein (P-gp), when administered orally alone and in combination with the CHOP regimen in patients with untreated non-Hodgkin's lymphoma and to determine whether zosuquidar.3HCL affects pharmacokinetics of doxorubicin and vincristine. Doses of CHOP remained constant and the doses of zosuquidar.3HCL were increased from 200 to 500 mg per dose. A total of 15 patients were treated at three dose levels. A target dose providing peak and trough levels compatible with prolonged modulation of P-gp function was obtained in patients receiving three doses of 500 mg of zosuquidar.3HCL p.o. At this dose level, toxicity was minimal and no enhancement of CHOP-related toxicity was observed. Zosuquidar.3HCL did not significantly affect the pharmacokinetics of doxorubicin and had moderate effects on the pharmacokinetics of vincristine. Zosuquidar.3HCL can be safely administered with CHOP therapy using a 24-h schedule.

Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine.[Pubmed:15257929]

Haematologica. 2004 Jul;89(7):782-90.

BACKGROUND AND OBJECTIVES: P-glycoprotein (P-gp) is a major cause of multidrug resistance (MDR) in acute myelogenous leukemia (AML) and is thought to contribute to the failure of chemotherapy. Zosuquidar trihydochloride (Z.3HCL) is a potent and selective inhibitor of P-gp which rapidly and effectively inhibits drug efflux. DESIGN AND METHODS: The aim of this study was to evaluate the clinical effects of Z.3HCL and determine its influence on P-gp activity. Sixteen AML patients were entered into a phase 1 dose ranging clinical trial of Z.3HCL, co-administered intravenously with daunorubicin and cytosine arabinoside (ARA-C). Clinical outcomes, toxicity abd adverse events were assessed. P-gp function was analyzed by flow cytometry. In vitro cytotoxicity was studied using the MTT assay. RESULTS: Eleven patients achieved a complete remission and one a partial remission with a median survival of 559 (range 38-906) days. Non-hematologic grade 3 and 4 toxicities were seen in 4 patients. Z.3HCL infusion was associated with rapid inhibition of Rh123 efflux in CD56+ cells in 16/16 patients and in CD33+ cells from 6/10 patients. The median inhibition was 95% for CD56+ cells and 85.25% for CD33+ cells was significantly elevated in 6/16 patients. The median IC50, using a MTT assay for daunorubicin, decreased significantly between Z.3HCL modulated and unmodulated cells (n=11,153 and 247 ng/mL respectively, p=0.01). INTERPRETATION AND CONCLUSIONS: The modulator Z.3HCL is a specific inhibitor of P-gp efflux and can be given safely to patients with AML in combination with induction doses of conventional cytotoxic drugs.

Stereochemistry of C-6 nucleophilic displacements on 1,1-difluorocyclopropyldibenzosuberanyl substrates. An improved synthesis of multidrug resistance modulator LY335979 trihydrochloride.[Pubmed:15497993]

J Org Chem. 2004 Oct 29;69(22):7653-60.

Studies of the displacement chemistry of 1,1-difluorocyclopropyldibenzosuberanyl alcohol 4 and its activated bromide derivative 6 have led to an improved approach to anti-2, a key precursor to LY335979 3HCl (1). Bromination of either syn-4 or anti-4 gave anti-oriented 6, indicating thermodynamically controlled product stereochemistry via a stabilized 1,1-difluorohomotropylium ion intermediate. Reaction of 6 with piperazine proceeded irreversibly to provide an isomeric mixture of piperazine products, with the syn:anti product ratio increased by solvent effects. Reaction of 6 with pyridine and pyrazine, on the other hand, gave anti-pyridinium and pyrazinium salts, respectively, apparently via equilibration of initially formed syn products. Reduction of pyrazinium salt 11 with lithium borohydride/TFA provided anti-2 unaccompanied by its syn isomer. A practical and expeditious approach to 1 was derived from these new results.

A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy.[Pubmed:15161679]

Clin Cancer Res. 2004 May 15;10(10):3265-72.

PURPOSE: Our intention was to (a) to investigate the safety and tolerability of a potent P-glycoprotein modulator, zosuquidar trihydrochloride (LY335979), when administered i.v. alone or in combination with doxorubicin, (b) to determine the pharmacokinetics of zosuquidar and correlate exposure to inhibition of P-glycoprotein function in a surrogate assay, and (c) to compare the pharmacokinetics of doxorubicin in the presence and absence of zosuquidar. PATIENTS AND METHODS: Patients with advanced malignancies who provided written informed consent received zosuquidar and doxorubicin administered separately during the first cycle of therapy and then concurrently in subsequent cycles. Zosuquidar was given i.v. over 48 h in a cohort-dose escalation manner until the occurrence of dose-limiting toxicity or protocol specified maximum exposure. Doxorubicin doses of 45, 60, 75 mg/m(2) were administered during the course of the trial. RESULTS: Dose escalation proceeded through 9 cohorts with a total of 40 patients. The maximal doses administered were 640 mg/m(2) of zosuquidar and 75 mg/m(2) of doxorubicin. No dose-limiting toxicity of zosuquidar was observed. Pharmacokinetic analysis revealed that, in the presence of zosuquidar at doses that exceeded 500 mg, there was a modest decrease in clearance (17-22%) and modest increase in area under the curve (15-25%) of doxorubicin. This change was associated with an enhanced leukopenia and thrombocytopenia but was without demonstrable clinical significance. The higher doses of zosuquidar were associated with maximal P-glycoprotein inhibition in natural killer cells. CONCLUSION: Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.

Novel non-peptide nociceptin/orphanin FQ receptor agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: design, synthesis, and structure-activity relationship of oral receptor occupancy in the brain for orally potent antianxiety drug.[Pubmed:19125610]

J Med Chem. 2009 Feb 12;52(3):610-25.

An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous systems in humans, primates, and rodents, and are involved in the integration of the emotional components in the brain; e.g., N/OFQ displays anxiolytic activity in the brain. For identifying orally potent anxiolytic, drug-design studies were performed with a series of 1,2-disubstituted benzimidazole derivatives, which resulted in the identification of various chemotypes of highly potent NOP selective full agonists in vitro with high or moderate NOP receptor occupancy in the mice brain per os such as 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole 1 (MCOPPB), the most potent novel non-peptide NOP full agonist in vitro and an orally potent anxiolytic in the mice.

Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an anxiolytic agent.[Pubmed:18319566]

J Pharmacol Sci. 2008 Mar;106(3):361-8. Epub 2008 Mar 5.

Nociceptin/orphanin FQ peptide (NOP)-receptor agonists have been shown to produce anxiolytic-like effects in rodents subjected to various behavioral assays. Recently, we developed a new nonpeptide agonist of the NOP receptor, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB), as an anxiolytic agent. MCOPPB has a high affinity for the human NOP receptor (pKi = 10.07 +/- 0.01) and selectivity for the NOP receptor over other members of the opioid receptor family: 12-, 270- and >1000-fold more selective for the NOP receptor than for the micro-, kappa-, and delta-receptor, respectively. In an ex vivo binding study, MCOPPB (10 mg/kg, p.o.) inhibited signaling through the NOP receptor in the mouse brain, suggesting that it penetrated into the brain after it was orally administered. In the mouse Vogel conflict test, MCOPPB (10 mg/kg, p.o.) and diazepam (3 mg/kg, p.o.) elicited anxiolytic-like effects, although MCOPPB produced a bell-shaped response curve. In addition, MCOPPB (10 mg/kg, p.o.) was still effective as an anxiolytic agent even after repeated administration for 5 days. MCOPPB at an oral dose of 10 mg/kg did not affect locomotor activity or memory, nor did it contribute to ethanol-induced hypnosis. On the other hand, the benzodiazepine-type anxiolytic agent diazepam caused memory deficits and enhanced ethanol-induced hypnosis. These findings suggest that MCOPPB - a compound with few adverse effects on the central nervous system - is a potential therapeutic agent for the treatment of anxiety.