28797-48-0Relevant articles and documents
Tricyclic Compounds as Selective Antimuscarinics. 2. Structure-Activity Relationships of M1-Selective Antimuscarinics Related to Pirenzepine
Eberlein, Wolfgang G.,Engel, Wolfgang W.,Trummlitz, Guenter,Schmidt, Guenter,Hammer, Rudolf
, p. 1169 - 1174 (1988)
In order to gain some insight into those structural features that control M1 selectivity, a selected set of pirenzepine analogues has been studied in which both the tricyclic ring system and the basic side chain have varied.Binding studies were conducted in rat tissue homogenates from cerebral cortex (M1) and gastric fundus (M2).The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of M1 receptor selectivity.Several derivatives, especially those with flexible side chains, i.e. high degree of freedom of rotation around single bonds, proved to be nonselective.Among semirigid compounds only those containing 6-membered ring systems (11, 13, 14, and 15) showed significant M1 selectivity.Principles of structure-activity and structure-selectivity are discussed.
MUSCARINIC ANTAGONISTS WITH PARP AND SIR MODULATING ACTIVITY AS CYTOPROTECTIVE AGENTS
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Page/Page column 21, (2010/02/15)
The present invention relates to generally to the cytoprotective activity of mixed muscarinic inhibition/PARP modulation and in particular to the use of dual inhibitors of M1 muscarinic receptor and poly(ADP-ribose) polymerase (PARP) as neuroprotective medicaments, particularly as medicaments for the prevention and/or treatment of neurological diseases. Particularly preferred compounds are condensed diazepinones, e.g. condensed benzodiazepinones such as pirenzepine or compounds which are metabolized to condensed benzodiazepinones such as olanzapine.
Functionalized congener approach to muscarinic antagonists: Analogues of pirenzepine
Karton,Bradbury,Baumgold,Paek,Jacobson
, p. 2133 - 2145 (2007/10/02)
The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7-10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors.
