PSYCHOTROPIC DRUGS AND RECEPTOR SENSITIVITY CHANGES

  • Richelson, Elliott, (PI)

Project: Research project

Description

The proposed research involves a multi-disciplinary approach to develop
novel psychotherapeutic agents that pass the blood-brain barrier to
stimulate the human neurotensin receptor. These agents may be potential
drugs for treatment of the diverse neuropsychiatric disorders of
schizophrenia and Alzheimer's type dementia. To achieve this goal, we
plan to use the cloned human neurotensin receptor stably expressed in a
transfected cell line to continue our work on two novel neurotensin
receptor agonists that we have synthesized. One compound represent an
intermediate step toward the synthesis of non-peptide neurotensin
agonists and was designed on the basis of our molecular modeling by
computer of neurotensin (8-13). The second, is an adamantane derivative
of one of our novel neurotensin (8-13) peptide analogs and appears to
penetrate the brain of mice. To learn more about the binding site(s) for
neurotensin and these novel compounds, we plan studies involving site-
directed mutagenesis of the human neurotensin receptor. These studies
will likely be feasible since, with DNA sequence information from the
cloned rat receptor, we have obtained to date by polymerase chain
reaction (PCR) (from a CDNA library of human substantia nigra, a rich
source of neurotensin receptors) and CDNA screening of a human library,
about 90% of the human neurotensin receptor open reading frame sequence.
At the amino acid level, there is about 87% identify in a 377 amino acid
overlap between the rat and human receptors. After obtaining the entire
sequence in a clone, we plan, as we have done with the cloned rat
receptor, to study the human neurotensin receptor in a transfected cell
line. In addition, with our excellent probe for the human neurotensin
receptor, we plan to study by in situ hybridization the expression of the
receptor in normal human brain and in Alzheimer's disease brains. To
characterize the expressed cloned human neurotensin receptor, we will do
radioligand binding studies with [3H]neurotensin and membranal
preparations from cells and measure neurotensin's effects on second
messenger (inositol phosphates and CAMP) synthesis by intact cells. Our
novel neurotensin receptor agonists will be tested in these assays with
the expressed human neurotensin receptor. Finally, we will test in mice
the effects of these compounds on sleep time induced by pentobarbital,
on body temperature, and on analgesia to characterize their in vivo
effects.
StatusFinished
Effective start/end date6/1/778/31/98

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Drug Receptors
Psychotropic Drugs
Arachidonic Acid
Thrombin
Neurotensin Receptors
Cholinergic Agents
Cyclic GMP
Bradykinin
Clone Cells
Bradykinin Receptors
Histamine Agonists
Radioligand Assay
neurotensin (8-13)
Hemostasis
Neuroblastoma
varespladib methyl
Synaptic Transmission
Gas Chromatography
Gas Chromatography-Mass Spectrometry
Histamine

ASJC

  • Medicine(all)