RESPONSES OF SUBPOPULATIONS OF MUSCARINIC RECEPTORS

Project: Research project

Description

Reduced cholinergic function in the central nervous system contributes to
memory disturbances, including those associated with senile dementia of the
Alzheimer type. Previous studies by ourselves and others have demonstrated
conclusively that distinct subtypes of muscarinic receptors are present in
varying proportions in different brain regions. Classical receptor theory
dictates that the most useful receptor classification schemes be based on
the affinities of antagonists. The only antagonist that displays
heterogeneous binding profiles and has been extensively characterized in
response assays is pirenzipine; therefore, there is some reason for concern
that the results obtained may reflect anomalous properties of this single
compound, rather than an underlying pharmacology. Further, the
characterizations may have been confounded by tissue-related differences,
as the different responses were studied in different tissues. This
proposal intends to correlate sophisticated assays of binding and response
in model in vitro systems so as to relate the responses to given
subpopulations. One line of investigation will evaluate multiple
muscarinic responses and receptor binding in parallel, in identical
preparations (neurally derived cell lines); thereby, the problems of
between-tissue differences will be eliminated and the affinities of a given
antagonist in the different response assays and binding assays can be
compared directly. A second approach will examine a single response in
regions of the brain that possess very different distributions of
subpopulations, as a test of the uniformity of the relationship between
response and receptor subtype. In both of these approaches, receptor
subtypes will be defined according to the affinities of pirenzipine and
other antagonists (e.g. gallamine, clozapine), characterized in our ongoing
evaluation of potentially selective muscarinic ligands. Furthermore, the
results of classical pharmacological methods, such as Schild analysis of
competitive antagonists, will be supplemented by an independent procedure:
selective protection of given subpopulation(s) of receptors from
irreversible blockade by alkylating antagonists. Selective protection is a
powerful technique that can also be used to determine the relationships
between the subpopulations defined by different selective ligands and to
evaluate the response characteristics of agonist-defined subpopulations.
It is expected that these studies will lead to the development of agents
with greater selectivity toward muscarinic subpopulations and that this
knowledge may foster the development of newer and safer approaches to the
enhancement of cognitive performance.
StatusFinished
Effective start/end date2/1/858/31/19

Funding

  • National Institutes of Health: $299,297.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $210,750.00
  • National Institutes of Health
  • National Institutes of Health: $308,490.00
  • National Institutes of Health
  • National Institutes of Health: $210,750.00
  • National Institutes of Health: $287,684.00
  • National Institutes of Health: $210,750.00
  • National Institutes of Health: $617,968.00
  • National Institutes of Health: $182,534.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $210,750.00
  • National Institutes of Health: $239,896.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $302,321.00
  • National Institutes of Health: $302,321.00
  • National Institutes of Health: $127,996.00

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Muscarinic Receptors
Cholinergic Agents
Allosteric Site
Ligands
Pharmacology
Brain
Pharmaceutical Preparations
Binding Sites
Alzheimer Disease
Gallamine Triethiodide
Allosteric Regulation
G-Protein-Coupled Receptors
Clozapine
Central Nervous System
Neurotransmitter Agents
Acetylcholine
Molecular Models
Muscarinic M1 Receptors
Central Nervous System Diseases
Safety