McLean Hospital 115 Mill Street Belmont, MA 02478
John L. Neumeyer, PhD, received his BS from Columbia University, and PhD in medicinal chemistry from the University of Wisconsin, Madison. He became a professor of medicinal chemistry and chemistry at Northeastern University in 1969, was appointed Matthews Distinguished Professor in1980, and was a Fulbright Scholar from 1975 to 1976. Dr. Neumeyer is a fellow of the American Association for the Advancement of Science, the American Association of Pharmaceutical Sciences, and the American Chemical Society.
Dr. Neumeyer has received the following awards: Achievement Award in Pharmaceutical and Medicinal Chemistry from the Academy of Pharmaceutical Sciences Research (1982); Marie Curie Award from the European Association of Nuclear Medicine (1992); Henry A. Hill Award for Outstanding Service to the Northeastern Section from the American Chemical Society (1998). In 2008, Dr. Neumeyer was inducted into the American Chemical Society Division of Medicinal Chemistry Hall of Fame.
Dr. Neumeyer’s Medicinal Chemistry Laboratory was founded in 1998 to focus on launching new medicines in a variety of specialties.
Recent developments include a medication to block the release of dopamine (a “feel good” brain chemical), which potentially reduces drug cravings in cocaine dependency. As a treatment for Parkinson’s disease—which is caused by a deficiency of dopamine—Dr. Neumeyer and his lab are working to develop effective oral medications that act like dopamine yet do not have serious side effects. Their template for drug design is apomorphine (a molecule synthesized from morphine), which incorporates dopamine in its structure.
In addition, the lab creates imaging compounds for brain scans—techniques that are rapidly expanding the reach of medical and scientific research. By “labeling” apomorphine and analogues with radioisotopes that are visible in brain images, they help clinicians diagnose certain conditions earlier and monitor the effectiveness of treatments.
Novel chemical entities can be used as molecular tools to modulate the activity of a variety of G-protein coupled receptors in the central nervous system.
In Dr. Neumeyer’s study on the development of mixed kappa and mu opioid receptor ligands as an alternative approach to cocaine abuse, kappa agonists seem to attenuate a number of neurobiological effects of cocaine. However, mixed kappa/mu agonists appear to offer some advantages as potential treatments for cocaine abuse. Both acute and chronic treatment with the mixed kappa/mu opioids—cyclorphan and its N-cyclobutylmethyl derivative (MCL-101, butorphan)—reduced cocaine self-administration. In addition, they produced fewer side effects than kappa-selective agonists. These promising results encouraged Dr. Neumeyer to further synthesize a series of novel modified morphinan analogues, based on the structures of cyclorphan and butorphan.
A number of brain receptors (and transporters) are linked to both the biological action of cocaine and various psychiatric disorders. Unfortunately, the functions of these proteins and their mechanisms of action are still largely unknown. To visualize these proteins, Dr. Neumeyer’s group is developing innovative imaging agents for PET, SPECT, and MRI scans. Such methods could help broaden the understanding of Parkinson’s disease, schizophrenia, attention deficit hyperactivity disorder (ADHD), drug addiction, and other common neuropsychiatric conditions. The lab’s focus is the synthesis and pharmacological evaluation of novel ligands for dopamine receptors and transporters as well as kappa and mu opioid agonists and antagonists.
Evidence suggests that the failure of dopamine agonists/antagonists or dopamine reuptake transporter inhibitors responsible for cocaine reward/reinforcement may be ascribed to their low selectivity for dopamine over serotonin or norepinephrine receptors. Although five subtypes of dopamine receptors have been found and cloned, their structures and functions are largely unknown. The lab’s efforts in the development of highly potent and selective ligands for dopamine receptor (transporter) or subtypes of dopamine receptor (D1, D2, D3, D4, D5) mainly focus on the synthesis and evaluation of novel ligands, which are selective D1 or D2 agonists. Such agents will be useful when labeled with radioactive isotopes for evaluating the etiology and progress of Parkinson’s disease and related neurological disorders in human brains.
Sromek AW, Si Y-G, Zhang T, George SR, Seeman P, Neumeyer JL. Synthesis and evaluation of fluorinated aporphines: potential positron emission tomography ligands for D2 receptors. ACS Medicinal Chemistry Letters 2011;2,189-194.
Ye N, Neumeyer JL, Baldessarini RJ, Zhen X, Zhang A. Update 1 of: Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chemical Reviews 2013;113,PR123-PR178.
Finnema S, Stepanov V, Nakao R, Sromek AW, Zhang T, Neumeyer JL, George SR, Seeman P, Stabin MG, Jonsson C, Farde L, Halldin C. 18F-MCL-524, an 18F-labeled dopamine D2 and D3 receptor agonist sensitive to dopamine: a preliminary PET study. Journal of Nuclear Medicine 2014;55(7):1164-1170.
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