- Tricyclic Compounds as Selective Antimuscarinics. 2. Structure-Activity Relationships of M1-Selective Antimuscarinics Related to Pirenzepine
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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.
- Eberlein, Wolfgang G.,Engel, Wolfgang W.,Trummlitz, Guenter,Schmidt, Guenter,Hammer, Rudolf
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- An intestinal gastric pirenzepine hydrochloride is an important intermediate for simple synthesis process (by machine translation)
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The invention discloses an intestinal gastric pirenzepine hydrochloride is an important intermediate for simple and convenient synthetic process, against the 5, 11 - dihydro - 11 - chloracetyl - 6 H - pyrido [2.3 - b] [1, 4] benzodiazepine - 6 - one synthetic, develops a piece of raw materials are simple and easy, simple operation of the synthesis process, in order to O-nitro benzoic acid and 2 - chloro - 3 - aminopyridine as a main raw material, five-step synthesis of the target compound, low cost, high yield, high purity, the final drug has far-reaching practical significance. (by machine translation)
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- MUSCARINIC ANTAGONISTS WITH PARP AND SIR MODULATING ACTIVITY AS CYTOPROTECTIVE AGENTS
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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.
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Page/Page column 21
(2010/02/15)
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- Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor
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Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.
- Tahtaoui, Chouaib,Parrot, Isabelle,Klotz, Philippe,Guillier, Fabrice,Galzi, Jean-Luc,Hibert, Marcel,Ilien, Brigitte
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p. 4300 - 4315
(2007/10/03)
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- Functionalized congener approach to muscarinic antagonists: Analogues of pirenzepine
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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.
- Karton,Bradbury,Baumgold,Paek,Jacobson
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p. 2133 - 2145
(2007/10/02)
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- Tricyclic Compounds as Selective Muscarinic Receptor Antagonists. 3. Structure-Selectivity Relationships in a Series of Cardioselective (M2) Antimuscarinics
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On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue.The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity.Qualitative structure-selectivity relationships point to the fact that it is the spartial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.
- Engel, Wolfhard W.,Eberlein, Wolfgang G.,Mihm, Gerhard,Hammer, Rudolf,Trummlitz, Guenter
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p. 1718 - 1724
(2007/10/02)
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- EXPERIMENTAL ANTIULCER AGENTS: N-SUBSTITUTED 2-(4-METHYL-1-PIPERAZINYL)ACETAMIDES AS PIRENZEPINE MODELS AND SOME RELATED COMPOUNDS
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Reactions of N-cyclohexyl-2-chloroacetamide, N-phenyl-2-chloroacetamide, N-(4-dimethylaminophenyl)-2-chloroacetamide, N-(2-nitrophenyl)-N-phenyl-2-chloroacetamide, its 3-nitrophenyl and 4-nitrophenyl analogues, N-(2-benzylphenyl)-2-chloroacetamide, 5-(chloroacetyl)dibenzazepine, and its 10,11-dihydro derivative with piperazine, 1-methylpiperazine, 2-(1-piperazinyl)ethanol, and 3-(1-piperazinyl)propanol resulted in compounds II, III, V -XV, XVIII, XXI, and XXIII, simple analogues of the antiulcer agent pirenzepine (I).Contributions to the syntheses and characterization of mianserin (XIX), bisnor analogue of imipramine (XXV), and pirenzepine (I) are presented.Two 2-aryl-2-(2-pyridyl)thioacetamides XXXVIII and XL were synthesized via nitriles XXXIX and XLI.Compounds XI (VUFB-17 104) and XXI (VUFB-17 113) were found to be rather effective as anti-ulcer agents and anticholinergics.
- Hulinska, Hana,Polivka, Zdenek,Jilek, Jiri,Sindelar, Karel,Holubek, Jiri,et al.
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p. 1820 - 1844
(2007/10/02)
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