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Mark 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 Adjunct Professor of Chemistry at Rensselaer and taught
over 30 graduate-level organic and medicinal chemistry courses.
Anti-cocaine Medications
The main goal of this research is to design, synthesize
and characterize potential medications to treat cocaine abuse
in humans. Our working hypothesis for this research is that
agents which release dopamine (DA) from the nucleus accumbens
(the pleasure seeking area of the human brain) promote drug-seeking
behavior and those which prevent release of DA prevent drug-seeking
behavior. A growing body of evidence exists indicating that
kappa-opioid agonists with varying activity at the mu-opioid
receptor are effective in reducing cocaine self-administration
in nonhuman primates. Cyclazocine, one of our lead compounds,
displays this receptor binding profile and is currently undergoing
clinical trials by NIDA for remediation of cocaine addiction.
Cyclazocine, however, is short acting in humans and animals
via O-glucuronidation. In hopes of identifying novel isosteric
replacements for the phenolic OH of cyclazocine, we recently
reported the synthesis and biological properties of 8-CAC. This
new cyclazocine analogue has a carboxamide group 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. We are
currently focused on exploring the structure-activity relationships
of this new series of carboxamido-substituted opiates and their
potential as anti-cocaine medications. (Collaborators: Dr. Jean
M. Bidlack and coworkers at University of Rochester; Funding:
NIH/NIDA and Albany Molecular Research, Inc.)
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)
Wentland, M. P.; Sun, X.; Ye, Y.; Lou, R.; Bidlack, J. M. Redefining
the Structure-Activity Relationships of 2,6-Methano-3-benzazocines.
II. 8-Formamidocyclazocine Analogues.Bioorgan. Med. Chem.
Lett. 2003, 13, 1911-1914.
Lou, R.; VanAlstine, M.; Sun, X.; Wentland, M. P. "Preparation
of N-Hydroxysuccinimido Esters via Palladium-Catalyzed Carbonylation
of Aryl Triflates and Halides." Tetrahedron Lett.
2003, 44, 2477-2480.
Wentland, M. P.; Ye, Y.; Cioffi, C. L.; Lou, R.; Zhou, Q.;
Xu, G.; Duan, W.; Dehnhardt, C. M.; Sun, X.; Cohen, D. J.; Bidlack,
J. M. "Syntheses and Opioid Receptor Binding Affinities
of 8-Amino-2,6-methano-3-benzazocines." J. Med. Chem.
2003, 46, 838-849.
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.
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