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Functional activity of new derivatives of dextromethorphan as allosteric inhibitors of α3β4 nicotinic acetylocholine receptor.

Joanna D. Kozak 1,  Dariusz Matosiuk 2,  Agnieszka Ligęza 2,  Irving W. Wainer 3,  Krzysztof Jóźwiak 1

1. Laboratory of Drug-Receptor Interaction, Medical University of Lublin, Lublin 20-950, Poland
2. Medical University, Faculty of Pharmacy, Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Staszica 6, Lublin 20-081, Poland
3. National Institute on Aging (NIA), 5600 Nathan Shock Dr, Baltimore, MD 21222, United States

Abstract
Dextromethorphan (DM) is well known the active ingredient in most over-the-counter cough medicines. DM is structurally closely related to levorphanol, codeine, and morphine, but unlike these opiates it has low affinity for opiate receptors and is not considered to be addictive [fig.1]. Its complex pharmacology led scientists to suugest several other potential uses( e.g., for a treatment for Huntington's and Parkinson's disease, stroke and ischemia, seizure disorders, and cocaine dependence). In our studies dextromethorphan and its metabolites were determined as noncopetitive antagionist of neuronal nicotinic acetylocholine receptors, in particular α3β4 subtype which is involved in regulation of dopaminergic pathways in brain sections responsible for addiction development. Extensive molecular modeling studies were performed in our laboratory which identified a binding site within a ion channel and allowed in silico

design of N-substituted derivatives of dextromethorphan. Some of these new desigs were synthesized and characterized structurally [Fig.1]. 

Fig. 1 The structure of dextromethorphan and selected synthesized derivatives.                      

In current research these compounds are tested for functional activity against α3β4 nAChR in electropfysiological assay. The aim of the study is to perform the in vitro tests for these substances using patch-clamp technique. The experiments are carried out on HEK-293 cells stably transfected with rat α3 and β4 neuronal nicotinic receptor genes. Ionic currnets in whole-cellconfiguration is measured using a fast drug delivery syetem DynaFlow. The cells are stimulated by 100μM nicotine in combination with increasin concentration of an inhibitor. The evoked current measurements allows determining sigmoidal drug-response curve and based on such logarithmic graph we can compute such parameters as EC50 for an agonist, IC50 for DM ant its derivatives, Hill coefficient, dissociation constant ect.

The DM as a potent antagonist of α3β4 neuronal nicotinic receptors could play a pivotal role in developing new more efficient therapy to aim on habenular-interpeduncular (Hb-IPN) system where the α3β4 subtype of nAChR is densely expressed. The most recent results strongly suggest that HB-IPN pathway is associated with withdrawal effect which is mainly responsible for failure in nicotine cessation therapies.

 

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Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Joanna D. Kozak
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-01 14:14
Revised:   2010-04-08 09:52