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1,3-dioxolane muscarinic antagonists modified at the cationic head
INFLUENCE OF A U X I L I A R Y AGENTS ON BIOTRANSFORMATION AND PHARMACOLOGICAL ACTIVITY OF TRANQUILIZER GIDAZEPAM. V P.Zherdev, G.B.Kolyvanov, A.A.Litvin, S.G.Otabekova Science Research Institute of Pharmacology Russian Academy o£ Medical Sciences, Baltiyskaya st-r. 8, 125315 Moscow, Russia. The experimental and clinical researches studying the pharmacokinetics of gidazepam - [(1-hydrazinocarbonyl)-methyl-7-brom-5-plSeny I- 1,2-d ihydr o-3H-1,4-benzodiazepine-2-on] showed that in organism the drug is active y metabolized with the Formation of" the 5asic metabohte desalkylgidazepam. The pharmacological. activity of" the unchanged druq is completely different from that of" its metabo[ite by tile absence of pronounced side effects. In this connection with the purpose to prepare an atipical tranquilizer, it was of interest to slow down the b otransformation of gidazepam in organism. This task was fulfilled by using different auxiliary agents. It was shown that a marked increase in unchanged d-rug concentrations in animal blood plasma and the absence of pronounced side effects can be observed Following drug administration in 4% solution of polyvinylpyrrolidone (PVP) a.s compared to 4% solitions of tween 80, PEG-400 and starch. An increase in concentratiens of high-molecular substances in aqueous solutions of gidazepam after oral administration tends to enlarge the extent of its desalkylation and to cause more pronounced and prolonged myorelaxative and sedative effects. The obtained as solic[ disperse system with PVP (1:4) prov de the possibility to prepare on this basis a drug form of cj dazepam that produce the pronounced anxiolytic action with minima s de effectsl
ATROPINE AND GLYCOPYRRONIUM SHOW SIMILAR BINDING PATTERNS TO MI, M2 AND M3 MUSCARINIC RECEPTOR SUBTYPES IN THE RAT, I. Bellid__Qo,A. Gomezand F. S&nchezde la Cuesta. Departmentof Pharmacologyand Clinical Therapeutics. School of Medicine,Universityof Malaga, Spain. Glycopyrroniumis purportedto be similarantisialagogueeffect, but less likelyto cause significanttachycardiathanatropineduringanaesthesia. Differentantimuscarinicreceptorselectivitypaterns could explain the differences.The aim of this investigationwas to detemine the possible selectivity of glycopyrroniumfor Mr, M2 and M3 muscarinic receptor subtypes.MuscarinicreceptorsubtypesinWistarrat forebrain,ventricle and submandibular3gland homogenates were ch@racterizedwith [3H]pirenzepine ([ H]-PIR) (forebrainI and [3H]-N-methylscopolamine ([3M]-NMS) (ventricle and submandibulary gland) by ligand binding studies. Inhibition of [3H]-PIR and [3Hi-NMS binding by nonlabelled compounds showed the following order i] forebrain: atropine > glycopyrrolate >>pirenzepine > HMSiD >> otenzepad, similar to the expectedorder of frequencyof M1 subtype;ii) ventricle:glycopyrrolate > atropine>> otenzepad > HHSiD > pirenzepine,similar to the expected order of frequency of M2 subtype; iii) submandibular gland: glycopyrrolate > atropine>> HHSiD >> pirenzepine> otenzepad,similar to the expected order of frequencyof M3 subtype. Glycopyrroniumshowed both high affinity and no selectivityto bound to M1 (Pki=9.00±0.12riM), M. (Pb=8 72+0 01 nM1 and M. (Pki=8.78±0.04nM) muscarinic receptor Z
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subtypes. These data do not support a discrtmnating properties of glycopynnnimbetweenmuscarinicreceptorssubtypes. (Dataobtainedfrom ventricle and submandibulargland is reproduced by pemission of the Editor of British Journal of Anaesthesia).
--50--
ANTAGONISTIC AFFINITY DIFFERENT SLrB~PES OF
PROFILE OF MUSCARINIC
IMPERIALINE RECEPTORS
ON
H. Akbulut I, O. ()zdemir:, $. Oktay 2 Departments of Pharmacology, Istanbul University School of Pharmacy I and Marmara University School of Medicine 2, Istanbul, Turkey. Eglen et al. (1992) have reported that the cervane alkaloid, Imperialine, differentiated between muscarinic M 2 and M s subtypes by a 10fold affinity difference in binding and functional studies although it could not differentiate between M 2 and putative M 4 sites according to binding experiments. It has been reported by (bzkutlu et al. (1993) on the basis of a variety of subtype preferring antagonists that the contractions of the guinea-pig gallbladder were mediated via M~-mus carinic receptors. In this study, the antagonistic affinity of Imperialine was assessed in vitro by using electrically
paced
rat
left
atria
(RLA) ,
guinea-pig ileum (GPI) and guinea-pig gallbladder (GPGB) preparations which contain M2, M 3 and putative M 4 subtypes, respectively. Imperialine antagonized the negative inotropy produced by carbachol (CCh) in RLA, and CChinduced contractions in GPI and GPGB with pA 2 values of 7.44+0.13, 6.62+0.12 and 7.14+_0.18 (Schild plot slopes of -0.95+0.09, -1.21+0.10 and -0.93+_0.10) respectively. The antagonistic profile of Imperialine demonstrates this compound to be an M2-selective antagonist which has intermediate affinity for M 4 and low affinity for M s receptors. Eg] en RM, Harris GC, Cox H, Sullivan AD, Stefanich E & Whiting RL: Naunyn-Schmiedeberg's Arch. Pharmaco!. 1992; 346: 144 Ozkutlu U, AlJcan I, Karah~n F, Onat F, Yemen B¢, Ulusoy NB & Oktay ~: Pharmacology 1993; 46: 308
1,3-DIOXOLANE MUSCARINIC ANTAGONISTS MODIFIED AT THE CATIONIC HEAD M.L. C i n g o l a n L a, L. Brasilib, U.GuliniC, A. PiergentiliC and W. Quaglia c alnstitute of Biomedical Sciences, Medical School, Via Ranieri, 6 0 1 0 0 Ancona; b D e p a r t m e n t o f Medicinal Chemistry, Via Carnpi 183, 4 1 1 0 0 Modena. CDepartment of Chemical Sciences, Via S. Agostino I, 62032 Camerino, Italy. For several years we have been involved in the study of the muscarinic receptor using the 1,3dioxolane nucleus as an useful tool for exploring the heterogeneity of this receptor. Since we assume the presence of distinct areas for t h e different muscarinic subtypes close to the anionic binding site of the receptor, we synthesized a series of antagonist related to 2,2-diphenyl-4[(dimethylamino)methyl]-I ,3-dioxolane, which have been modified at the cationic head. The compounds have been tested in vitro in rabbit vas deferens, guinea pig heart and ileum for M1, M2 and M3 subtype activity, respectively. Our r e s u l t s show t h a t some c o m p o u n d s d i s p l a y some selectivity among the studied subtypes.
ATROPINE AND GLYCOPYRRONIUM SHOW SIMILAR BINDING PATTERNS TO MI, M2 AND M3 MUSCARINIC RECEPTOR SUBTYPES IN THE RAT, I. Bellid__Qo,A. Gomezand F. S&nchezde la Cuesta. Departmentof Pharmacologyand Clinical Therapeutics. School of Medicine,Universityof Malaga, Spain. Glycopyrroniumis purportedto be similarantisialagogueeffect, but less likelyto cause significanttachycardiathanatropineduringanaesthesia. Differentantimuscarinicreceptorselectivitypaterns could explain the differences.The aim of this investigationwas to detemine the possible selectivity of glycopyrroniumfor Mr, M2 and M3 muscarinic receptor subtypes.MuscarinicreceptorsubtypesinWistarrat forebrain,ventricle and submandibular3gland homogenates were ch@racterizedwith [3H]pirenzepine ([ H]-PIR) (forebrainI and [3H]-N-methylscopolamine ([3M]-NMS) (ventricle and submandibulary gland) by ligand binding studies. Inhibition of [3H]-PIR and [3Hi-NMS binding by nonlabelled compounds showed the following order i] forebrain: atropine > glycopyrrolate >>pirenzepine > HMSiD >> otenzepad, similar to the expectedorder of frequencyof M1 subtype;ii) ventricle:glycopyrrolate > atropine>> otenzepad > HHSiD > pirenzepine,similar to the expected order of frequency of M2 subtype; iii) submandibular gland: glycopyrrolate > atropine>> HHSiD >> pirenzepine> otenzepad,similar to the expected order of frequencyof M3 subtype. Glycopyrroniumshowed both high affinity and no selectivityto bound to M1 (Pki=9.00±0.12riM), M. (Pb=8 72+0 01 nM1 and M. (Pki=8.78±0.04nM) muscarinic receptor Z
1
"
-
"
J
.
•
subtypes. These data do not support a discrtmnating properties of glycopynnnimbetweenmuscarinicreceptorssubtypes. (Dataobtainedfrom ventricle and submandibulargland is reproduced by pemission of the Editor of British Journal of Anaesthesia).
--50--
ANTAGONISTIC AFFINITY DIFFERENT SLrB~PES OF
PROFILE OF MUSCARINIC
IMPERIALINE RECEPTORS
ON
H. Akbulut I, O. ()zdemir:, $. Oktay 2 Departments of Pharmacology, Istanbul University School of Pharmacy I and Marmara University School of Medicine 2, Istanbul, Turkey. Eglen et al. (1992) have reported that the cervane alkaloid, Imperialine, differentiated between muscarinic M 2 and M s subtypes by a 10fold affinity difference in binding and functional studies although it could not differentiate between M 2 and putative M 4 sites according to binding experiments. It has been reported by (bzkutlu et al. (1993) on the basis of a variety of subtype preferring antagonists that the contractions of the guinea-pig gallbladder were mediated via M~-mus carinic receptors. In this study, the antagonistic affinity of Imperialine was assessed in vitro by using electrically
paced
rat
left
atria
(RLA) ,
guinea-pig ileum (GPI) and guinea-pig gallbladder (GPGB) preparations which contain M2, M 3 and putative M 4 subtypes, respectively. Imperialine antagonized the negative inotropy produced by carbachol (CCh) in RLA, and CChinduced contractions in GPI and GPGB with pA 2 values of 7.44+0.13, 6.62+0.12 and 7.14+_0.18 (Schild plot slopes of -0.95+0.09, -1.21+0.10 and -0.93+_0.10) respectively. The antagonistic profile of Imperialine demonstrates this compound to be an M2-selective antagonist which has intermediate affinity for M 4 and low affinity for M s receptors. Eg] en RM, Harris GC, Cox H, Sullivan AD, Stefanich E & Whiting RL: Naunyn-Schmiedeberg's Arch. Pharmaco!. 1992; 346: 144 Ozkutlu U, AlJcan I, Karah~n F, Onat F, Yemen B¢, Ulusoy NB & Oktay ~: Pharmacology 1993; 46: 308
1,3-DIOXOLANE MUSCARINIC ANTAGONISTS MODIFIED AT THE CATIONIC HEAD M.L. C i n g o l a n L a, L. Brasilib, U.GuliniC, A. PiergentiliC and W. Quaglia c alnstitute of Biomedical Sciences, Medical School, Via Ranieri, 6 0 1 0 0 Ancona; b D e p a r t m e n t o f Medicinal Chemistry, Via Carnpi 183, 4 1 1 0 0 Modena. CDepartment of Chemical Sciences, Via S. Agostino I, 62032 Camerino, Italy. For several years we have been involved in the study of the muscarinic receptor using the 1,3dioxolane nucleus as an useful tool for exploring the heterogeneity of this receptor. Since we assume the presence of distinct areas for t h e different muscarinic subtypes close to the anionic binding site of the receptor, we synthesized a series of antagonist related to 2,2-diphenyl-4[(dimethylamino)methyl]-I ,3-dioxolane, which have been modified at the cationic head. The compounds have been tested in vitro in rabbit vas deferens, guinea pig heart and ileum for M1, M2 and M3 subtype activity, respectively. Our r e s u l t s show t h a t some c o m p o u n d s d i s p l a y some selectivity among the studied subtypes.