CONFORMATIONALLY RESTRAINED BETA-BLOCKING OXIME ETHERS .2. SYNTHESIS AND BETA-ADRENERGIC PROPERTIES OF DIASTEREOISOMERIC ANTI AND SYN 2-(5'-(3'-ARYL-SUBSTITUTED)ISOXAZOLIDINYL)-N-ALKYLETHANOLAMINES

被引:7
作者
BALSAMO, A [1 ]
BRESCHI, MC [1 ]
CHIELLINI, G [1 ]
LUCACCHINI, A [1 ]
MACCHIA, M [1 ]
MARTINELLI, A [1 ]
MARTINI, C [1 ]
NARDINI, C [1 ]
ORLANDINI, E [1 ]
ROMAGNOLI, F [1 ]
ROSSELLO, A [1 ]
机构
[1] UNIV PISA,IST POLICATTEDRA DISCIPLINE BIOL,I-56100 PISA,ITALY
关键词
ADRENERGIC DRUG; BETA-BLOCKING AGENT; 2-(5'-(3'-ARYL-SUBSTITUTED)ISOXAZOLIDINYL)ETHANOLAMINE;
D O I
10.1016/0223-5234(94)90108-2
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The diastereoisomeric 2-(5'-(3'-aryl)isoxazolidinyl) ethanolamines 1c-h-4c-h were synthesized as analogs of the corresponding P-blocking isoxazolines unsubstituted on the aromatic ring 1a-4a, with the aim of checking the effects on the adrenergic properties of the insertion of a methoxy group or a chlorine atom in the ortho, meta or para position of the phenyl ring of 1a-4a. The relative configurations of 1c-h-4c-h were assigned on the basis of their H-1-NMR spectral characteristics. The new isoxazolines 1c-h-4c-h were tested for their affinity towards beta(1)- and beta(2)-adrenoceptors by radioligand binding experiments; compounds showing the highest affinity were also assayed for their beta-adrenergic activity by functional tests on isolated preparations. The results showed that most of the new compounds (1c-h-4c-h) possess a slightly better capacity to interact with the beta-receptors, compared with the corresponding analogs unsubstituted on the phenyl ring (1a-4a), and that the substitution that leads to compounds with the best properties is the one with the chlorine atom. Quantum mechanical calculations carried out in order to look for possible correlations between the beta-adrenergic properties and the conformational and electronic characteristics induced by the presence of the substituents on the phenyl ring of compounds of types 1-4 do not suggest any reasonable explanation for the trend of the affinity data.
引用
收藏
页码:855 / 867
页数:13
相关论文
共 17 条
[1]   CONFORMATIONALLY RESTRAINED BETA-BLOCKING OXIME ETHERS - SYNTHESIS AND BETA-ADRENERGIC PROPERTIES OF DIASTEREOISOMERIC ANTI AND SYN 2-(5'-ISOXAZOLIDINYL)-ETHANOLAMINES [J].
BALSAMO, A ;
BRESCHI, MC ;
CHINI, M ;
DOMIANO, P ;
GIANNACCINI, G ;
LUCACCHINI, A ;
MACCHIA, B ;
MACCHIA, M ;
MANERA, C ;
MARTINELLI, A ;
MARTINI, C ;
MARTINOTTI, E ;
NIERI, P ;
ROSSELLO, A .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1992, 27 (08) :751-764
[2]  
BALSAMO A, 1991, 10 CONV NAZ DIV CHIM, P137
[3]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[4]  
CONNOLLY ML, 1985, MS MOL SURFACE PROGR
[5]   SILYL NITRONATES, NITRILE OXIDES, AND DERIVED 2-ISOXAZOLINES IN ORGANIC-SYNTHESIS - FUNCTIONALIZATION OF BUTADIENE, A NOVEL ROUTE TO FURANS AND 2-ISOXAZOLINES AS AN ALTERNATIVE TO ALDOL-TYPE CONDENSATIONS [J].
DAS, NB ;
TORSSELL, KBG .
TETRAHEDRON, 1983, 39 (13) :2247-2253
[6]   CGP 20712-A - A USEFUL TOOL FOR QUANTITATING BETA-1-ADRENOCEPTOR AND BETA-2-ADRENOCEPTORS [J].
DOOLEY, DJ ;
BITTIGER, H ;
REYMANN, NC .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1986, 130 (1-2) :137-139
[7]   NORADRENALINE MODULATES SMOOTH-MUSCLE ACTIVITY OF THE ISOLATED INTRAVESICAL URETER OF THE PIG THROUGH DIFFERENT TYPES OF ADRENOCEPTORS [J].
HERNANDEZ, M ;
PRIETO, D ;
SIMONSEN, U ;
RIVERA, L ;
BARAHONA, MV ;
GARCIASACRISTAN, A .
BRITISH JOURNAL OF PHARMACOLOGY, 1992, 107 (04) :924-931
[8]  
KIM JN, 1992, J ORG CHEM, V57, P6489
[9]   SYNTHESIS, ANTIINFLAMMATORY ACTIVITY AND MOLECULAR-ORBITAL STUDIES OF A SERIES OF BENZYLIDENEAMINOXYPROPIONIC ACIDS SUBSTITUTED ON THE PHENYL RING [J].
LAPUCCI, A ;
MACCHIA, M ;
MARTINELLI, A ;
NENCETTI, S ;
ORLANDINI, E ;
ROSSELLO, A ;
BALDACCI, M ;
SOLDANI, G ;
MENGOZZI, G .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1994, 29 (01) :33-39
[10]  
LARSEN KE, 1984, TETRAHEDRON, V40, P2985