Professor, Department of Chemistry and Chemical Biology
Rensselaer Polytechnic Institute

Education:
Ph.D., Rice University, 1970

Career Highlights:
Wentland completed his graduate studies in synthetic organic chemistry in 1970 at Rice University working with the late Professor Robert V. Stevens. He then went to Sterling Winthrop Inc. where he conducted drug discovery research in the medicinal chemistry department for 24 years; his last positions were Sterling Winthrop Fellow and Oncology Discovery Co-Chair. In 1994, he joined the chemistry faculty at Rensselaer. During the period 1971-1994, he was an adjunct professor of chemistry at Rensselaer and taught over 30 graduate-level organic and medicinal chemistry courses.

Research Areas:
Medications to Treat Addictive Disorders
The main goal of our research is to design, synthesize and characterize potential medications to treat cocaine abuse and other addictive disorders in humans. Our working biological hypothesis is that agents that release dopamine from the nucleus accumbens (the pleasure seeking area of the human brain) promote drug-seeking behavior and those which prevent release of dopamine prevent drug-seeking behavior.  A growing body of evidence exists indicating that this reward pathway can be modulated by opioid G protein-coupled receptor ligands.  Cyclazocine, our original lead, is a mu opioid receptor partial agonist and kappa agonist and is effective in reducing cocaine self-administration in nonhuman primates. However, it is short acting in humans and animals via O-glucuronidation of its phenolic OH group.  In hopes of identifying novel isosteric replacements for the phenolic OH of cyclazocine, we reported in 2001 the synthesis and biological properties of 8-CAC. This new cyclazocine analogue has a carboxamide group (CONH₂) in place of the phenolic OH and displays unexpectedly high affinity for opioid receptors and has a 15 hour duration of action in a mouse antinociception model. For comparison, cyclazocine's duration of action at the same dose of 1 mg/kg (ip) is 2 hours.  Subsequent structure-activity relationship studies on 8-CAC and other carboxamido-substituted opioids showed exceptionally high affinity [K_i values as low as 0.052 nM (mu)] for opioid receptors is seen when the carboxamide group is flanked by a hydroxyl group.

In September 2006 Rensselaer signed a license agreement granting Alkermes Inc. - a biotechnology company based in Massachusetts - exclusive rights to the opioid compounds discovered by our team.  In December 2008, Alkermes announced that they had initiated a Phase 1 clinical study to assess safety and tolerability of one member (ALKS 33) of Rensselaer's opioid library.  ALKS 33 which has potential to treat alcohol dependence and other reward disorders demonstrates promising human pharmacokinetic properties such as rapid oral absorption, high plasma concentrations and a long half-life.  In the second half of 2009, Alkermes expects to start a Phase 1 clinical study of another member (RDC-1036) of Rensselaer's opioid library.   We continue to explore the structure-activity relationships of this new series of carboxamido-substituted opioids and their potential for the treatment of addictive disorders in humans. (Collaborators: Dr. Jean M. Bidlack and coworkers at University of Rochester and Alkermes, Inc.  Current funding: NIH/NIDA)

Identification of Novel Analgesic Targets
A new class of pain-relieving drugs derived from histamine antagonists has been discovered. Our main goal in this project is to design and synthesize novel brain-penetrating analogues of our lead series and to identify an emerging structure-activity relationship. (Collaborators: Dr. Lindsay B. Hough and coworkers at the Albany Medical College; Funding: NIH/NIDA).

Selected Publications:

Wentland, M. P.; Lou, R.; Lu, Q.; Bu, Y.; Denhardt, C.; Jin, J.; Ganorkar, R.; VanAlstine, M. A.; Guo, C.; Cohen, D. J.; Bidlack, J. M. " Syntheses of novel high affinity ligands for opioid receptors" Bioorg. Med. Chem. Lett. 2009, 19, 2289–2294.

Wentland, M. P.; Lu, Q.; Ganorkar, R.; Zhang, S.-Z.; Jo, S.; Cohen, D. J.; Bidlack, J. M. " Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 7. Syntheses and opioid receptor properties of cyclic variants of cyclazocine." Bioorg. Med. Chem. Lett. 2009, 19, 365-368.

Wentland, M. P.; Lou, R.; Lu, Q.; Bu, Y.; VanAlstine, M. A.; Cohen, D. J.; Bidlack, J. M. "Syntheses and opioid receptor binding properties of carboxamido-substituted opioids."  Bioorg. Med. Chem. Lett. 2009, 19, 203-208.

Wentland, M. P.; Sun, X., Cohen, D. J.; Bidlack, J. M. "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 6. Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine."  Bioorg. Med. Chem. 2008, 16, 5653-5664.

Hough, L. B.; Nalwalk, J. W.; Phillips, J. G.; Kern, B.; Shan, Z.; Wentland, M. P.; Esch, I. J. P. Janssen, E.; Barr, T.; Stadel, R. “CC12, A High Affinity Ligand for ³H-Cimetidine Binding, is an Improgan Antagonist.” Neuropharmacology, 2007, 52, 1244-1255.

Wentland, M. P.;  VanAlstine, M.; Kucejko, R.;  Lou, R; Cohen, D. J.; Parkhill, A. L.; Bidlack, J. M. "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines.  Part 4. Opioid receptor binding properties of 8-[N-(4'-phenyl)-phenethyl)­carboxamido] analogues of cyclazocine and EKC."  J. Med. Chem.  2006, 49, 5635-5639.

Wentland, M. P.; Lu, Q.; Lou, R.; Knapp, B. I.; Bidlack, J. M.  ^"Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone." Bioorg. Med. Chem. Lett.  2005, 15, 2107-2110.

Bidlack, J. M.; Cohen, D. J.; McLaughlin, J. P.; Lou, R.; Ye, Y.; Wentland, M. P. "8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan."  J. Pharmacol. Exp. Ther. 2002, 302, 374-380.

Wentland, M. P.; Lou, R.; Ye, Y.; Cohen, D. J.; Richardson, G. P.; Bidlack, J. M. ^"8-Carboxamidocyclazocine Analogues: Redefining the Structure-Activity Relationships of 2,6-Methano-3-benzazocines." Bioorg. Med. Chem. Lett. 2001, 11, 623-626.