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Title: Muscarinic receptor subtype selectivity of novel heterocyclic QNB analogues

In an effort at synthesizing centrally-active subtype-selective antimuscarinic agents, the authors derivatized QNB (quinuclidinyl benzilate), a potent muscarinic antagonist, by replacing one of the phenyl groups with less lipophilic heterocyclic moieties. The displacement of ({sup 3}H)-N-methyl scopolamine binding by these novel compounds to membranes from cells expressing ml - m4 receptor subtypes was determined. Most of the novel 4-bromo-QNB analogues were potent and slightly selective for ml receptors. The 2-thienyl derivative was the most potent, exhibiting a 2-fold greater potency than BrQNB at ml receptors, and a 4-fold greater potency than BrQNB at ml receptors, and a 4-fold greater potency at m2 receptors. This compound was also considerably less lipophilic than BrQNB as determined from its retention time on C18 reverse phase HPLC. This compound may therefore be useful both for pharmacological studies and as a candidate for a radioiodinated SPECT imaging agent for ml muscarinic receptors in human brain.
Authors:
; ; ;  [1]
  1. (George Washington Univ. Medical Center, Washington, DC (USA))
Publication Date:
OSTI Identifier:
5583540
Resource Type:
Journal Article
Resource Relation:
Journal Name: Life Sciences; (USA); Journal Volume: 48:24
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; PARASYMPATHOLYTICS; CHEMICAL PREPARATION; PARASYMPATHOMIMETICS; RECEPTORS; BIOCHEMICAL REACTION KINETICS; BRAIN; RADIOPHARMACEUTICALS; SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY; TRACER TECHNIQUES; TRITIUM COMPOUNDS; AUTONOMIC NERVOUS SYSTEM AGENTS; BODY; CENTRAL NERVOUS SYSTEM; COMPUTERIZED TOMOGRAPHY; DIAGNOSTIC TECHNIQUES; DRUGS; EMISSION COMPUTED TOMOGRAPHY; HYDROGEN COMPOUNDS; ISOTOPE APPLICATIONS; KINETICS; LABELLED COMPOUNDS; MEMBRANE PROTEINS; NERVOUS SYSTEM; ORGANIC COMPOUNDS; ORGANS; PROTEINS; REACTION KINETICS; SYNTHESIS; TOMOGRAPHY 550201* -- Biochemistry-- Tracer Techniques; 550601 -- Medicine-- Unsealed Radionuclides in Diagnostics