ABSTRACT
A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4-benzthiepine ring or seven-membered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1,4-benzoxazine ring increased the antagonistic activities (dimethyl > methyl > dihydro > phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3,4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,2, 4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki = 0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold--Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.
Subject(s)
Amides/chemical synthesis , Oxazines/chemical synthesis , Serotonin Antagonists/chemical synthesis , Amides/pharmacology , Animals , Brain Chemistry/drug effects , Granisetron/pharmacokinetics , Hemodynamics/drug effects , Magnetic Resonance Spectroscopy , Male , Molecular Conformation , Oxazines/pharmacology , Rats , Rats, Wistar , Receptors, Serotonin/chemistry , Receptors, Serotonin/drug effects , Reflex/drug effects , Reflex/physiology , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
The stereostructures of cumingianosides A-F, a series of triterpene glucosides with a 14,18-cycloapoeuphane skeleton, have been established by X-ray crystallographic analysis on an aglycone [1c] the acid hydrolysate of cumingianoside A [1], which is a potent cytotoxic triterpene against MOLT-4 human leukemia cells with an EC50 value of < 0.00625 microM. The 14,18-cyclopropane ring in cumingianoside A [1] was opened under acidic conditions in two different directions to give compounds with an apoeuphane skeleton and a dammarane skeleton. Furthermore, it was found that subsequent hydrolysis yielded not only an aglycone with an apoeuphane skeleton [1c] but also an apo-rearrangement product [1d].
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Glucosides/chemistry , Leukemia, Experimental/drug therapy , Triterpenes/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Crystallography, X-Ray , Glucosides/isolation & purification , Glucosides/pharmacology , Humans , Hydrolysis , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Plant Leaves/chemistry , Triterpenes/isolation & purification , Triterpenes/pharmacology , Tumor Cells, CulturedABSTRACT
Investigation of the roots of Patrinia scabra afforded two new iridolactones, patriscabrol and isopatriscabrol. Their structures have been established by extensive analysis of their NMR spectra and an X-ray crystallographic analysis of patriscabrol. Four monoglucosides of each iridolactone were also isolated together with an apioside of glucosidic patriscabrol.
Subject(s)
Glycosides/chemistry , Lactones/chemistry , Plants, Medicinal/chemistry , Carbohydrate Sequence , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Drugs, Chinese Herbal/chemistry , Glycosides/isolation & purification , Lactones/isolation & purification , Magnetic Resonance Spectroscopy , Molecular Sequence DataABSTRACT
Mosapramine (1) is a new neuroleptic drug with an asymmetric carbon atom (8a) in its imidazopyridine ring. The enantiomers of this agent were synthesized to compare their biological activities, such as antiapomorphine activity, affinity for dopamine D2 receptor and acute toxicity. The key intermediates, (R)-(-)- and (S)-(+)-2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a]pyridine- 3-spiro-4'-piperidines, were prepared by optical resolution of the corresponding (+/-)-compound and were treated with 3-chloro-5-(3-methanesulfonyloxypropyl)-10,11-dihydro-5H-dibenz[b, f]azepine to afford (R)-(-)-1 and (S)-(+)-1, respectively. There were few differences in the examined biological activities of the two enantiomers as their dihydrochlorides.
Subject(s)
Antipsychotic Agents/pharmacology , Apomorphine/antagonists & inhibitors , Benzazepines/pharmacology , Receptors, Dopamine D2/metabolism , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Behavior, Animal/drug effects , Benzazepines/chemical synthesis , Benzazepines/chemistry , Benzazepines/pharmacokinetics , Dogs , Drug Interactions , Female , Male , Mice , Motor Activity/drug effects , Rats , Receptors, Dopamine D2/drug effects , Stereoisomerism , Vomiting/chemically inducedABSTRACT
Two enantiomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-one 7-oxide ((+/-)-1: Y-23684) were synthesized in high yields by asymmetric oxidation of the synthetic precursor (2) using modified Sharpless reagent. Among the oxidants tested, cumene hydroperoxide (CHP) gave the highest optical and chemical yields, while tert-butyl, tert-amyl, and 1,1,3,3-tetramethylbutyl hydroperoxides did not show such high enantio-selectivities. The absolute configuration of (+)-1 enantiomer synthesized from 2, Ti(O-iso-Pr)4, (-)-diethyl tartarate, and CHP was determined to be S by X-ray crystallographic analysis. Both enantiomers, S-(+)-1 and R-(-)-1, and (+/-)-1 had approximately equivalent in vivo activities to antibicuculline test in mice and anticonflict test in rats, although S-( + )-1 showed about three times higher affinity to benzodiazepine receptor than R-(-)-1 in [3H]diazepam binding assay.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Benzothiepins/chemical synthesis , Pyridazines/chemical synthesis , Animals , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Benzothiepins/pharmacology , Binding, Competitive/drug effects , Conflict, Psychological , In Vitro Techniques , Male , Mice , Mice, Inbred Strains , Pyridazines/pharmacology , Rats , Rats, Inbred Strains , Receptors, GABA-A/drug effects , StereoisomerismABSTRACT
The stereoisomers of some N-[(1-alkyl-2-pyrrolidinyl)methyl]-5- sulfaoylbenzamides (3-8) and -2,3-dihydrobenzofuran-7-carboxamides (9-18) were prepared to compare their dopamine D2 receptor binding affinities (in vitro) and inhibitory effects on apomorphine-induced hyperactivity (in vivo). In the 1-ethyl substituted compounds of the two series, the stereoisomers with S absolute configuration at the 2-position of the pyrrolidine moiety (S enantiomer 3 and 2S diastereomers 9 and 10) were more potent in both of the above activities than those with R absolute configuration (R enantiomer 4 and 2R diastereomers 11 and 12, respectively), whereas the R enantiomer (8) was more potent than the S enantiomer (7) in the 1-n-hexyl-substituted-benzamides and the 2R diastereomers (15, 16, and 18) were more potent than the 2S diastereomers (13, 14, and 17) in the 1-n-butyl- and 1-n-hexyl-2,3-dihydrobenzofuran-7-carboxamides. It was found that the stereospecificity of the compound activities altered from the S configuration to the R configuration as the 1-alkyl side chain became longer in the two series. How these stereoisomers meet the configurational requirements to interact with the dopamine D2 receptors is also discussed.
Subject(s)
Benzamides/chemical synthesis , Dopamine Antagonists , Motor Activity/drug effects , Receptors, Dopamine/drug effects , Animals , Benzamides/chemistry , Benzamides/pharmacology , Corpus Striatum/metabolism , Indicators and Reagents , Molecular Conformation , Molecular Structure , Optical Rotation , Rats , Receptors, Dopamine/metabolism , Receptors, Dopamine D2 , Spiperone/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 2,3-dihydrobenzofuran-7-carboxamides, presenting a stabilized intramolecular hydrogen bond, was synthesized and evaluated in pharmacological models for antipsychotic activity. Among them, N-[(1-butyl-2-pyrrolidinyl)methyl]-2-methyl-5-sulfamoyl-2, 3-dihydrobenzofuran-7-carboxamide (15) showed an atypical neuroleptic profile similar to that of sulpiride (1) and more lipophilic properties than 1. Compound 15 was 11 times more potent in antagonistic activity on apomorphine-induced hyperactivity in mice (ED50 = 30 mg/kg, p.o.) and stronger in potentiation of methamphetamine lethality in rats than 1, while it was as weak in inhibitory activity of apomorphine-induced stereotype in rats (ED50 greater than 500 mg/kg, p.o.) as 1. On the other hand, N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methyl-5-methylthio-2, 3-dihydrobenzofuran-7-carboxamide (30) showed a classical neuroleptic profile with a potency comparable to haloperidol in antagonistic activity on apomorphine-induced hyperactivity in mice (ED50 = 0.65 mg/kg, p.o.). The structure-activity relationships were also discussed.
