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  - 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  -