个人简介

Ph.D., Organic Chemistry, Rice University, 1970 B.S., Chemistry, Central Connecticut State University, 1966

研究领域

Medicinal/Organic

Discovery of Samidorphan, a medication currently in multiple Phase 2 and Phase 3 clinical trials: The main goal of our research is to design, synthesize and characterize oral, long-acting modulators of opioid G protein-coupled receptors (GPCRs) as medications to treat cocaine abuse and other central nervous system disorders in humans. A common structural feature of the large majority of opioids is a phenolic-OH group (see prototypic opioid structure below) that plays a crucial role in molecular recognition via H-bonding to a histidine residue of an opioid GPCR. For many opioids, however, this OH group is responsible for poor oral bioavailability and/or short half-life via O-glucuronidation. In 2001, we published the first report that a carboxamide group (CONH2) was an effective replacement for this prototypic phenolic-OH group of opioids. In addition to high affinity binding to opioid GPCRs, certain carboxamido-substituted opioids have much improved pharmacokinetic properties (relative to their phenolic-OH counterparts) as a consequence of high metabolic stability. Since 2001, our research group has focused on capitalizing on this discovery to achieve our main goal. Our first-generation opioid modulator in this series was 8-carboxamidocyclazocine (8-CAC) and a next generation agent is samidorphan (formerly referred to as ALKS 33). Our publications describing these discoveries as well as a wealth of structure-activity relationship data are catalogued in the PubMed link found below. In September, 2006 Rensselaer signed a license agreement granting Alkermes Inc. - a biotechnology company now based in Ireland - exclusive rights to a library of opioid compounds discovered by our team. Alkermes recently announced the initiation of multiple phase 3 clinical studies of ALKS 5461 (samidorphan in combination with buprenorphine) for treatment of patients with major depressive disorder. The U.S. Food and Drug Administration (FDA) has granted Fast Track status for ALKS 5461. Alkermes also announced the initiation of multiple phase 2 clinical studies of ALKS 3831, a novel oral atypical antipsychotic drug candidate designed to be a broad spectrum treatment for schizophrenia. ALKS 3831 is composed of samidorphan in combination with the established antipsychotic drug, olanzapine. See the following press releases from Alkermes for details: Alkermes Announces Positive Results From Study of ALKS 5461 for Treatment of Major Depressive Disorder Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder Alkermes Announces Positive Results of Phase 2 Clinical Trial of ALKS 3831 in Schizophrenia Collaborators: Dr. Jean M. Bidlack and coworkers at the Univ. of Rochester and Alkermes, Inc. Acknowledgments: This research was supported by the National Institute of Drug Abuse of the National Institutes of Health under award numbers DA12180 and KO5-DA00360. Funding from AMRI, Inc. is also gratefully acknowledged. Design and Synthesis of MW06-25, a Novel Probe to Study the Pathways of Morphine's Pain-relieving Properties. As part of a large collaborative effort headed by Dr. Lindsay Hough of the Albany Medical College, a report in Nature Neuroscience describes a neuronal P450 epoxygenase that mediates the pain-relieving properties of morphine. A two-tiered approached was used. The first involved a novel transgenic mutant mouse with brain neuron-specific reductions in P450 activity; compared with controls, these mice showed highly attenuated morphine antinociception. The second was a pharmacologic approach where our research group at Rensselaer designed and synthesized MW06-25, a brain P450 arachidonate epoxygenase inhibitor. MW06-25 produced a similar (to the transgenic mouse) block of morphine antinociception in mice. Collaborators: Dr. Lindsay B. Hough and coworkers at the Center for Neuropharmacology and Neuroscience, Albany Medical College. Acknowledgments: This research was supported by the National Institute of Drug Abuse of the National Institutes of Health under award number DA03816.

近期论文

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Antinociceptive activity of CC44, a biotinylated improgan congener. Hoerbelt P, Nalwalk JW, Phillips JG, Wentland MP, Shan Z, Hough LB. Eur J Pharmacol. 2013 Aug 15;714(1-3):464-71. doi: 10.1016/j.ejphar.2013.06.041. Epub 2013 Jul 5. PMID: 23834775. Select item 23434225 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis, characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors. VanAlstine MA, Wentland MP, Alvarez J, Cao Q, Cohen DJ, Knapp BI, Bidlack JM. Bioorg Med Chem Lett. 2013 Apr 1;23(7):2128-33. doi: 10.1016/j.bmcl.2013.01.117. Epub 2013 Feb 8. PMID: 23434225. Select item 23142613 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: oxygenated N-(2-[1,1'-biphenyl]-4-ylethyl) analogues of 8-CAC. Wentland MP, Jo S, Gargano JM, VanAlstine MA, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7340-4. doi: 10.1016/j.bmcl.2012.10.081. Epub 2012 Oct 27. PMID: 23142613. Select item 22869755 Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Porter DC, Farmaki E, Altilia S, Schools GP, West DK, Chen M, Chang BD, Puzyrev AT, Lim CU, Rokow-Kittell R, Friedhoff LT, Papavassiliou AG, Kalurupalle S, Hurteau G, Shi J, Baran PS, Gyorffy B, Wentland MP, Broude EV, Kiaris H, Roninson IB. Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13799-804. doi: 10.1073/pnas.1206906109. Epub 2012 Aug 6. PMID: 22869755. Select item 25068100 Cytochrome P450 2C24: Expression, Tissue Distribution, High-Throughput Assay, and Pharmacological Inhibition. Yang J, VanAlstine MA, Phillips JG, Wentland MP, Hough LB. Acta Pharm Sin B. 2012 Apr;2(2):137-145. PMID: 25068100. Select item 21316152 Brain P450 epoxygenase activity is required for the antinociceptive effects of improgan, a nonopioid analgesic. Hough LB, Nalwalk JW, Yang J, Conroy JL, VanAlstine MA, Yang W, Gargano J, Shan Z, Zhang SZ, Wentland MP, Phillips JG, Knapp BI, Bidlack JM, Zuiderveld OP, Leurs R, Ding X. Pain. 2011 Apr;152(4):878-87. doi: 10.1016/j.pain.2011.01.001. PMID: 21316152. Select item 20139973 Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling. Conroy JL, Fang C, Gu J, Zeitlin SO, Yang W, Yang J, VanAlstine MA, Nalwalk JW, Albrecht PJ, Mazurkiewicz JE, Snyder-Keller A, Shan Z, Zhang SZ, Wentland MP, Behr M, Knapp BI, Bidlack JM, Zuiderveld OP, Leurs R, Ding X, Hough LB. Nat Neurosci. 2010 Mar;13(3):284-6. doi: 10.1038/nn.2497. Epub 2010 Feb 7. PMID: 20139973. Select item 19282177 Syntheses of novel high affinity ligands for opioid receptors. Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2289-94. doi: 10.1016/j.bmcl.2009.02.078. Epub 2009 Feb 25. PMID: 19282177. Select item 19091564 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 7: syntheses and opioid receptor properties of cyclic variants of cyclazocine. Wentland MP, Lu Q, Ganorkar R, Zhang SZ, Jo S, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2009 Jan 15;19(2):365-8. doi: 10.1016/j.bmcl.2008.11.076. Epub 2008 Nov 24. PMID: 19091564. Select item 19027293 Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2009 Jan 1;19(1):203-8. doi: 10.1016/j.bmcl.2008.10.134. Epub 2008 Nov 7. PMID: 19027293. Select item 18417347 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine. Wentland MP, Sun X, Cohen DJ, Bidlack JM. Bioorg Med Chem. 2008 May 15;16(10):5653-64. doi: 10.1016/j.bmc.2008.03.066. Epub 2008 Mar 30. PMID: 18417347. Select item 17935988 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 5. Opioid receptor binding properties of N-((4'-phenyl)-phenethyl) analogues of 8-CAC. VanAlstine MA, Wentland MP, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2007 Dec 1;17(23):6516-20. Epub 2007 Sep 29. PMID: 17935988. Select item 17336343 CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist. Hough LB, Nalwalk JW, Phillips JG, Kern B, Shan Z, Wentland MP, de Esch IJ, Janssen E, Barr T, Stadel R. Neuropharmacology. 2007 Apr;52(5):1244-55. Epub 2007 Jan 20. PMID: 17336343. Select item 16942039 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 4. Opioid receptor binding properties of 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogues of cyclazocine and ethylketocycalzocine. Wentland MP, VanAlstine M, Kucejko R, Lou R, Cohen DJ, Parkhill AL, Bidlack JM. J Med Chem. 2006 Sep 7;49(18):5635-9. PMID: 16942039. Select item 16216240 Antinociceptive, brain-penetrating derivatives related to improgan, a non-opioid analgesic. Hough LB, Nalwalk JW, Lu Q, Shan Z, Svokos K, Wentland MP, Montero MJ. Eur J Pharmacol. 2005 Oct 17;522(1-3):38-46. Epub 2005 Oct 10. PMID: 16216240. Select item 15863314 Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 3: 8-Thiocarboxamido and 8-thioformamido derivatives of cyclazocine. Wentland MP, Sun X, Bu Y, Lou R, Cohen DJ, Bidlack JM. Bioorg Med Chem Lett. 2005 May 16;15(10):2547-51. PMID: 15863314. Select item 15808478 Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone. Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack JM. Bioorg Med Chem Lett. 2005 Apr 15;15(8):2107-10. PMID: 15808478. Select item 15588733 Effects of the mixed-action kappa/mu opioid agonist 8-carboxamidocyclazocine on cocaine- and food-maintained responding in rhesus monkeys. Stevenson GW, Wentland MP, Bidlack JM, Mello NK, Negus SS. Eur J Pharmacol. 2004 Dec 15;506(2):133-41. PMID: 15588733. Select item 14757849 Kappa-opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells. Gekker G, Hu S, Wentland MP, Bidlack JM, Lokensgard JR, Peterson PK. J Pharmacol Exp Ther. 2004 May;309(2):600-6. Epub 2004 Feb 2. PMID: 14757849. Select item 14730897 Synthesis and pharmacology of 8-amino-3-[(tetrahydro-2-furanyl)methyl] benzomorphan. Zhou Q, Duan WH, Cohen DJ, Bidlack JM, Wentland MP. Yao Xue Xue Bao. 2003 Oct;38(10):748-53. PMID: 14730897