Drugs online research references
J Med Chem. 1991 Jul;34(7):2133-45.
Functionalized congener approach to muscarinic antagonists: analogues of pirenzepine.
Karton Y, Bradbury BJ, Baumgold J, Paek R, Jacobson KA.
Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
The M1-selective muscarinic receptor antagonist pirenzepine 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.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2066986&dopt=Abstract
Life Sci. 1984 Sep 3;35(10):1069-76.
Inhibitory effects of quinidine on rat heart muscarinic receptors.
Waelbroeck M, De Neef P, Robberecht P, Christophe J.
Quinidine inhibited binding of the labelled agonist [3H]oxotremorine M [( 3H]Oxo-M) and the labelled antagonist [3H]N-methylscopolamine [( 3H]NMS) to rat heart muscarinic receptors. Kinetic studies demonstrated that quinidine decreased the association rates (I50: 4 and 7.5 microM) and dissociation rates (I50: 100 and 68 microM) of [3H]Oxo-M and [3H]NMS, with different potencies. These cooperative effects explained the low Hill coefficients and apparent selectivity of quinidine competition curves.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6482646&dopt=Abstract
Life Sci. 1994;54(23):1777-83.
Interaction of iodinated quinuclidinyl benzilate enantiomers with M3 muscarinic receptors.
Hiramatsu Y, Eckelman WC, Baum BJ.
Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
We examined the interaction of 3-quinuclidinyl-4-iodobenzilate enantiomers, (RR)- and (SS)-IQNB, relatively receptor-active and -inactive, respectively, with M3-muscarinic receptors (mAChRs) in rat parotid acinar cells in vitro. This stereospecific antagonist pair has often been used for in vivo studies of mAChRs. There was a 16-fold difference in the ability of (RR)- and (SS)-IQNB to bind in vitro to mAChRs; Ki values estimated by competition with N-methylscopolamine were 5.3 and 84.2 nM, respectively. However, the ability of these antagonists to inhibit carbachol-stimulated inositol trisphosphate formation (Ki values determined by Schild analyses) was more similar, 16.3 and 47.7 nM, respectively for (RR)- and (SS)-IQNB. These data suggest that while it may be useful to employ this antagonist pair to evaluate some mAChR subtypes in vivo, it is difficult to use them in studies of M3-mAChRs.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8196491&dopt=Abstract
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