TY - JOUR A1 - Dörje, F. A1 - Wess, J. A1 - Lambrecht, G. A1 - Tacke, Reinhold A1 - Mutschler, E. A1 - Brann, M. R. T1 - Antagonist binding profiles of five cloned human muscarinic receptor subtypes N2 - A variety of muscarinic antagonists are currently used as tools to pharmacologically subclassify muscarinic receptors into M\(_1\), M\(_2\) and M\(_3\) subtypes. ln the present study I we have determined the affinity proflies of several of these antagonists at five cloned human muscarinic receptors (m1-m5) stably expressed in Chinesehamster ovary cells (CHO-K1). At all five receptorsl the (R)-enantiomers of trihexyphenidyl and hexbutinol displayed considerably higher affinities (up to 525-fold) than their corresponding (S)-isomers. The stereoselectivity ratios [inhibition constant( S)/inhibition constant(R)] for both pairs of enantiomers were lowest at m2 receptors, suggesting that less stringent configurational demands are made by this receptor subtype. The "M\(_1\)-selective" antagonist (R)-trihexyphenidyl displayed high affinities for m1 and m4 receptors. The "M\(_2\)-selective" antagonists himbacinel (±}-5, 11-dihydro-11-1[(2-[(dipropylamino)methyl]-1- piperidinyllethyl)amino]carbonyii-6H-pyrido(213-b)(1 ~4)benzodiazepine- 6-one (AF-DX 384)1 11-(14-[4-(diethylamino)butyl)-1-piperidinyll acetyl)-5~ 11-dihydro-6H-pyrido(2~3-b) (1~4)benzodiazepine-6-one (AQ-RA 741) and (+K11-(12-[(diethylamino)methyl]-1-piperidinyll acetyl)-5~ 11-di-hydro-6H-pyrido(2~3-b)(1,4)benzodiazepine-6-one (AF-OX 250; the (+)-enantiomer of AF-DX 116] exhibited high affinities for m2 and m41 intermediate affinities for m1 and m3 and low affinities for m5 receptors. This selectivity profile was most prominent for AQ-RA 7 41 I which displayed 195- and 129-fold higher affinities for m2 and m4 receptors than for mS receptors. The "M\(_3\)-selective" antagonist (±)-p-fluoro-hexahydro-sila-difenidol hydrochloride (pFHHsiD) exhibited high affinity for m1 I m3 and m4 receptors. 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) bound with up to 7 -fold higher affinities to m1 I m31 m4 and m5 receptors than to m2 receptors. Although none of the tested antagonists showed more than 2-fold selectivity for one subtype over all other subtypes, each receptor displayed a unique antagonist binding profile. KW - Anorganische Chemie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64113 ER - TY - JOUR A1 - Dörje, F. A1 - Friebe, T. A1 - Tacke, Reinhold A1 - Mutschler, E. A1 - Lambrecht, G. T1 - Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus N2 - The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M\(_1\) (rabbit vas deferens), M\(_2\) (guinea-pig atria) and M\(_3\) receptors (guinea-pig ileum). The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD\(_2\) = 5.73) were competitively antagonized by pirenzepine (pA\(_2\) = 7.04), AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl] acetyl]- 5,11-dihydro-6H -pyrido[2,3-b][1 ,4]benzo. diazepin-6-one) (pA\(_2\) = 6.96), himbacine (pA\(_2\) = 7.92), methoctramine (pA\(_2\) = 7.52), 4-DAMP (4-diphenylacetoxy- N-methylpiperidine methiodide) (pA\(_2\) = 8.87) and sila-hexocyclium (pA\(_2\) = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M\(_1\), M\(_2\) or M\(_3\) receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M\(_4\) receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M\(_4\) receptors. KW - Anorganische Chemie KW - Muscarinic receptors KW - M4 receptors KW - Guinea-pig uterus KW - Pirenzepine KW - Methoctramine KW - Sila-hexocyclium Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64071 ER - TY - JOUR A1 - Bungardt, E. A1 - Vockert, E. A1 - Feifel, R. A1 - Moser, U. A1 - Tacke, Reinhold A1 - Mutschler, E. A1 - Lambrecht, G. A1 - Suprenant, A. T1 - Characterization of muscarinic receptors mediating vasodilation in guinea-pig ileum submucosal arterioles by the use of computer-assisted videomicroscopy N2 - Muscarinic receptors of rcsistance vessels (submucosal artcrioles, outside diametcr 50-75 J,Lm) from the guinea-pig small intestinc were invcstigatcd in vitro using a computcr-assisted vidcomicroscopy system (Diamtrak <~t ). The muscarinic receptor which mediates vasodilation of prccontractcd [U-46619 (300 nM) or (- )-noradrcnaline (1 0 J.L M)] artcriolcs was characterized with scveral muscarinic agonists and subtypc-sclectivc antagonists. Thc following agonists all produccd cquivalent maximum vasodilation (given in rank ordcr of potency): acctylcholinc = arccaidinc propargyl cstcr (APE) > oxotremorine = ( ± )-muscarinc = ( ± )-mcthacholinc > carbachol > 4-[[N-{4-chlorophenyl)carbamoyl]oxy]-2-hutynyltrimcthylammonium iodide (4-CI-McN-A- 343). 4-([N-(3-ChlorophcnyD-carbamoyl)oxy]-2-butynyltrimcthylammonium chloride (McN-A-343) and N-ethyl-guvacinc propargyl ester (NEN-APE) produccd minimal or no artcriolar vasodilation. Thc muscarinic antagonists pircnzcpinc, ( ± )-5,11-dihydro-11- [[[2-[2-((dipropylamino)methyl}-1-pipcridinyl]ethyl]amino ]-carbonyi]-6H-pyrido(2,3-h)( 1 ,4)-benzodiazcpin-6-onc (AF-DX 384 ), 11- [[ 4-[4-(dicthylamino)butyl]-1-piperidinyl]acetyl]-5, ll-dihydro-6H-pyrido(2.3-h)( 1,4 )-bcnzodiazepin-6-onc (AQ-RA 741 ), p-fluorohexahydro- sila-difcnidol (p-F-HHSiD), 4-diphcnylacetoxy-N-methylpipcridine mcthiodidc (4-DAMP) and (R)- and (S)hexahydro- difcnidol [(R)-HHD, (S)-HHD] shifted thc muscarinc, mcthacholinc or carbachol dosc-rcsponsc curve to the right in a compctitive manner. Schildanalysis of the data yicldcd pA\(_2\) valucs for pircnzcpinc (6.74/6.9), AF-DX 384 (6.72), AQ-RA 741 (6.58), p-F-HHSiD (7.53/7.57), 4-DAMP (9.06), (R)-HHD (7.88/8.32) and (S)-HHD (5.52/5.88). Thus, it can he concluded that submucosal arteriolcs posscss only the M\(_3\) functional muscarinic reccptor, the activation of which causcs hlood vcsscl dilation. The preparation dcscribcd is considcrcd to be a valuable now bioassay for pharmacological investigations of drug actions at muscarinic receptors in the peripheral vascular system. KW - Anorganische Chemie KW - Muscarinic receptor subtypes; Muscarinic rcceptor agonists (M 1-selective) KW - Muscarinic receptor antagonists (M 3-selective) KW - Vidcomicroscopy Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64206 ER - TY - JOUR A1 - Ackermann, J. A1 - Tacke, Reinhold A1 - Wannagat, U. A1 - Koke, U. A1 - Meyer, F. T1 - Derivate des 1-(4-Chlorphenyl)silacyclohexans mit 3-(Diethylamino)propyl- und 2-(Diethylamino)ethyl-Gruppierungen T1 - Derivatives of 1-(4-Chlorophenyl)silacyclobexane with 3-(Diethylamino)propyl- and 2-(Diethylamino)etbyl Groups N2 - Die Darstellung der Verbindungen 3a (sowie 3b) und 10, die sich vom 1-(4-Chlorphenyl)-1-(2~ diethylaminoethoxy)silacyclohexan (Sila-Chlorphencyclan, II a) ableiten, wird beschrieben. Die Verbindung 3 b wurde pharmakologisch und toxikologisch untersucht. Die biologischen Eigen· schaften von 3b wurden mit denen von Ila (sowie Chlorphencyclan) und seinem Hydrochiarid Ilb verglichen. N2 - The preparation of the compounds 3a (and 3b) and 10, which derive from 1-(4-chlorophenyl)-1· (2-diethylaminoethoxy)silacyclohexane (sila-chlorophencyclane, II a). is described. Compound 3 b has been investigated pharmacologically and toxicologically. The biological properties of 3 b and those of ßa (and chlorophencyclane) and its hydrochloride Ilb are compared. KW - Anorganische Chemie Y1 - 1979 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63621 ER - TY - JOUR A1 - Ackermann, J. A1 - Tacke, Reinhold A1 - Wannagat, U. A1 - Koke, U. A1 - Meyer, F. T1 - Sila-Analoga des Chlorphencyclans T1 - Sila Analogues of Chlorphencyclane N2 - Sila-Chlorphencyclan (8b), ein Sila-Analogon des Chlorphencyclans (8a), die Derivate 7 und 9, deren Ammoniumsalze 11, 12, 13 und 14b, das Hydrolyseprodukt 10 sowie die Vorstufen 3-6 wurden erstmalig dargestellt. Die neuen Verbindungen wurden in ihren chemischen und physikalischen Eigenschaften charakterisiert, ihre Struktur wurde sichergestellt. Chlorphencyclan, Sila-Chlorphencyclan und einige seiner Derivate wurden vergleichend pharmakologisch und toxikologisch untersucht. N2 - Silachlorphencyclane (8b), a sila analogue of chlorphencyclane (8a), the derivatives 7 and 9, their amrnonium salts 11, 12, 13 and 14b, the product of hydro Iysis 10, as weil as the precursors ~ were synthesized. The new compounds were characterized by their chemical and physical properties. The pharmacological and toxicological properties of chlorphencyclane, silachlorphencyclane and some derivatives were investigated. KW - Anorganische Chemie Y1 - 1980 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63633 ER -