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Bodnar AL, Cortes-Burgos LA, Cook KK, Dinh DM, Groppi VE, Hajos M, Higdon NR, Hoffmann WE, Hurst RS, Myers JK, Rogers BN, Wall TM, Wolfe ML, Wong E. Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors. J Med Chem. 2005 Feb 24 ; 48(4):905-8. Pubmed Abstract

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Primary Papers: Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors.

Comment by:  Ann Olincy
Submitted 5 July 2006
Posted 5 July 2006

This compound looks promising because it has good bioavailability and passes through the blood-brain barrier. It differs from DMXB-A in that it is a full agonist, which some people believe targets the α7 nicotinic receptor more fully, but also may have more problems with desensitization, which is not tested in this paper. They administer the drug to animals that are pretreated with amphetamine to cause a sensorimotor gating deficit, and thereby an animal model of schizophrenia. (I favor the use of DBA mice, which are abnormal in their gating because genetically they have fewer nicotinic receptors, as is the case with people with schizophrenia.) The authors are able to correct the gating deficit with their drug. However, they do not then let the deficit become abnormal (or artificially induce the abnormality again) and then give a second dose of their drug to see if they can again get a response, which would show that the receptor does not desensitize and the drug will work with repeated dosing. This is the problem with nicotine. We were able to get a second response with DMXB-A, and Karen Stevens has this kind of data in a paper on DMXB-A in mice (Stevens et al., 1998). This has not been true with other nicotinic compounds (Stevens and Wear, 1997). Finally, it is important to note that this is in animal models; who knows what it will do in humans?

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Related News: Nicotinic Receptor Agonist Shows Promise in Pilot Study

Comment by:  Robert W. Buchanan
Submitted 5 July 2006
Posted 5 July 2006

In light of the limitations of first- and second-generation antipsychotics and other pharmacological agents for the treatment of cognitive impairments in schizophrenia, the demonstration of an acute benefit of DMXB-A for cognitive performance and sensory gating is of considerable potential interest. Patients with schizophrenia are characterized by a broad range of cognitive impairments (Nuechterlein et al., 2004). These impairments have been shown to be a major determinant of poor functional outcome (Green et al., 2004). The NIMH has made a substantial commitment to facilitate the development of new pharmacological treatments for cognitive impairments through their funding of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) initiatives. The MATRICS process selected the α7 nicotinic receptor as one of the top targets for the treatment of cognitive impairments in patients with schizophrenia (Geyer and Tamminga, 2004).

In the current study, 12 subjects with schizophrenia were administered DMXB-A, an α7 nicotinic receptor partial agonist. The study was designed to assess the proof of concept that increased stimulation of the α7 nicotinic receptor would enhance performance on a cognitive battery and improve sensory gating, as measured by the P50 dual click paradigm. There is extensive preclinical and clinical rationale for this approach, but few drugs are available to directly assess the efficacy of the approach. The results clearly support the benefit of this approach, but a number of questions will need to be addressed in future studies before the ultimate utility of this approach is known. The most important issue is whether the acute efficacy observed with essentially a single dose will translate to a persistence of an effect with chronic drug administration. Tachyphylaxis develops rapidly with repeated stimulation of the α7 nicotinic receptor. Preclinical data suggest that this may not be an issue with DMXB-A, but long-term exposure data are required to directly address this issue. Second, two DMXB-A doses were evaluated. The results were different between the two doses, but how different is unclear, because of the small sample size. Preclinical data suggest that α7 nicotinic receptor partial agonists may show an inverse u-shaped response curve. The loss of efficacy at higher doses underscores the importance and potential difficulty in delineating the most effective dose range. Third, subjects who used nicotine products in the last month were excluded from the study. Patients with schizophrenia who do not smoke cigarettes are in the minority, and perhaps represent less than a third of the total population. The question of whether the beneficial effect of the drug would generalize to patients who smoke cigarettes will eventually need to be evaluated. Finally, the most pronounced effect was observed for the RBANS attention index. This effect is consistent with previous studies of acute nicotine administration in patients with schizophrenia. Future studies will need to evaluate whether the effect of DMXB-A is largely limited to attention or whether it will have significant benefit for other cognitive domains.

In summary, the demonstration that the acute administration of DMXB-A produces improved performance on a neuropsychological battery is an important first step in developing a novel therapeutic approach for one of the most critical areas of schizophrenia therapeutics.

References:

Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004; 72: 29-39. Abstract

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;7 2: 41-51. Abstract

Geyer MA, Tamminga CA. Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects. Psychopharm. 2004; 174: 1-2.

View all comments by Robert W. Buchanan

Related News: Nicotinic Receptor Agonist Shows Promise in Pilot Study

Comment by:  Patricia Estani
Submitted 6 July 2006
Posted 6 July 2006
  I recommend the Primary Papers