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Alzheimer’s and Parkinson’s Disease

Volume 29 of the series Advances in Behavioral Biology pp 551-556

Sulfonyl Fluorides as Possible Therapeutic Agents in Alzheimer’s Disease: Structure/Activity Relationships as CNS Selective Cholinesterase Inhibitors

  • D. E. MossAffiliated withDepartment of Psychology, University of TexasDepartment of Chemistry, University of Texas at El Paso
  • , L. A. RodriguezAffiliated withDepartment of Psychology, University of TexasDepartment of Chemistry, University of Texas at El Paso
  • , W. C. HerndonAffiliated withDepartment of Psychology, University of TexasDepartment of Chemistry, University of Texas at El Paso
  • , S. P. VincentiAffiliated withDepartment of Psychology, University of TexasDepartment of Chemistry, University of Texas at El Paso
  • , M. L. CamarenaAffiliated withDepartment of Psychology, University of TexasDepartment of Chemistry, University of Texas at El Paso

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Abstract

Senile dementia of the Alzheimer’s type (SDAT) is a disease that produces gross pathological changes in the brain. However, it has also been recently associated with specific changes in neurotransmitters such as somatostatin (Davies, Katzman and Terry, 1980; Rossor et al., 1980; Rogers and Morrison, 1984), amino acids (Arai, Kobayashi, Ichimiya, Kosaka and Iizuka, 1984) and acetylcholine (Davies and Maloney, 1976; Whitehouse et al., 1982). Although SDAT is not a disorder of a single neurotransmitter, deterioration of cholinergic function in the CNS appears to be correlated with dementia. For example, loss of the cholinergic system related to the nucleus basalis of Meynert (nbM) is associated with dementia in other disorders including Parkinson’s disease (Nakano and Hirano, 1984), parkinsonism-dementia complex of Guam, and boxer’s dementia (Nakano and Hirano, 1983). It is the apparent association between deterioration of the cholinergic system and dementia that is the basis for the cholinergic strategies for treating SDAT (e.g., Davies, 1981; Bartus, Dean, Beer and Lippa, 1982). In fact, physostigmine, a cholinesterase2 inhibitor that acts within the CNS as well as peripherally, has been reported to produce clinical improvement in tests with SDAT patients (e.g., Davis and Mohs, 1982; Brinkman and Gershon, 1983). This limited success has led to interest in developing a system for delivering cholinergic drugs directly into the CNS (Harbaugh, Roberts, Coombs, Saunders and Reeder, 1984) as well as the development of new long-lasting carbamate cholinesterase inhibitors that may have improved efficacy (Weinstock, Razin and Chorev, this volume).