Muscarinic receptor subtype selectivity of novel heterocyclic QNB analogues.
In an effort at synthesizing centrally-active subtype-selective antimuscarinic agents, we derivatized QNB (quinuclidinyl benzilate), a potent muscarinic antagonist, by replacing one of the phenyl groups with less lipophilic heterocyclic moieties. The displacement of [3H]-N-methyl scopolamine binding by these novel compounds to membranes from cells expressing m1-m4 receptor subtypes was determined. Most of the novel 4-bromo-QNB analogues were potent and slightly selective for m1 receptors. The 2-thienyl derivative was the most potent, exhibiting a 2-fold greater potency than BrQNB at m1 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.
Baumgold
J
J
Radiology Department, George Washington University Medical Center, Washington, D.C. 20037.
Cohen
V I
VI
Paek
R
R
Reba
R C
RC
D001667:Binding, Competitive; D002460:Cell Line; D015394:Molecular Structure; D019832:N-Methylscopolamine; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism
D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C069205:quinuclidinyl-2-thienyl-4-bromobenzilate; D011813:Quinuclidinyl Benzilate; D019832:N-Methylscopolamine