Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure

被引:71
作者
Campiani, G
Cappelli, A
Nacci, V
Anzini, M
Vomero, S
Hamon, M
Cagnotto, A
Fracasso, C
Uboldi, C
Caccia, S
Consolo, S
Mennini, T
机构
[1] UNIV SIENA, DIPARTIMENTO FARMACOCHIM TECNOL, I-53100 SIENA, ITALY
[2] UNIV PARIS 06, INSERM, U288, F-75634 PARIS 13, FRANCE
[3] IST RIC FARMACOL MARIO NEGRI, I-20127 MILAN, ITALY
关键词
D O I
10.1021/jm970376w
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptors, being agonists and antagonists, respectively. In functional studies ([C-14]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.
引用
收藏
页码:3670 / 3678
页数:9
相关论文
共 21 条
  • [1] NOVEL, POTENT, AND SELECTIVE 5-HT3 RECEPTOR ANTAGONISTS BASED ON THE ARYLPIPERAZINE SKELETON - SYNTHESIS, STRUCTURE, BIOLOGICAL-ACTIVITY, AND COMPARATIVE MOLECULAR-FIELD ANALYSIS STUDIES
    ANZINI, M
    CAPPELLI, A
    VOMERO, S
    GIORGI, G
    LANGER, T
    HAMON, M
    MERAHI, N
    EMERIT, BM
    CAGNOTTO, A
    SKORUPSKA, M
    MENNINI, T
    PINTO, JC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (14) : 2692 - 2704
  • [2] COMMON PHARMACOLOGICAL AND PHYSICOCHEMICAL PROPERTIES OF 5-HT3 BINDING-SITES IN THE RAT CEREBRAL-CORTEX AND NG 108-15 CLONAL CELLS
    BOLANOS, FJ
    SCHECHTER, LE
    MIQUEL, MC
    EMERIT, MB
    RUMIGNY, JF
    HAMON, M
    GOZLAN, H
    [J]. BIOCHEMICAL PHARMACOLOGY, 1990, 40 (07) : 1541 - 1550
  • [3] CACCIA S, 1990, ACTA PHARM JUGOSL, V40, P441
  • [4] POLYCONDENSED HETEROCYCLES .7. A CONVENIENT SYNTHESIS OF PYRROLO[1,2-A]QUINOXALINE DERIVATIVES BY INTRAMOLECULAR AROMATIC NUCLEOPHILIC DISPLACEMENT
    CAMPIANI, G
    NACCI, V
    CORELLI, F
    ANZINI, M
    [J]. SYNTHETIC COMMUNICATIONS, 1991, 21 (15-16) : 1567 - 1576
  • [5] DECREASE OF BRAIN ACETYLCHOLINE-RELEASE IN AGING FREELY-MOVING RATS DETECTED BY MICRODIALYSIS
    CHUN, FW
    BERTORELLI, R
    SACCONI, M
    PEPEU, G
    CONSOLO, S
    [J]. NEUROBIOLOGY OF AGING, 1988, 9 (04) : 357 - 361
  • [6] COHEN ML, 1989, J PHARMACOL EXP THER, V248, P197
  • [7] CONSOLO S, 1994, J NEUROCHEM, V62, P2254
  • [8] DETERMINATION OF ENDOGENOUS ACETYLCHOLINE-RELEASE IN FREELY MOVING RATS BY TRANSSTRIATAL DIALYSIS COUPLED TO A RADIOENZYMATIC ASSAY - EFFECT OF DRUGS
    CONSOLO, S
    WU, CF
    FIORENTINI, F
    LADINSKY, H
    VEZZANI, A
    [J]. JOURNAL OF NEUROCHEMISTRY, 1987, 48 (05) : 1459 - 1465
  • [9] SIMULTANEOUS ANALYSIS OF FAMILIES OF SIGMOIDAL CURVES - APPLICATION TO BIOASSAY, RADIOLIGAND ASSAY, AND PHYSIOLOGICAL DOSE-RESPONSE CURVES
    DELEAN, A
    MUNSON, PJ
    RODBARD, D
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1978, 235 (02): : E97 - E102
  • [10] CHARACTERISTICS OF [C-14] GUANIDINIUM ACCUMULATION IN NG 108-15 CELLS EXPOSED TO SEROTONIN 5-HT3 RECEPTOR LIGANDS AND SUBSTANCE-P
    EMERIT, MB
    RIAD, M
    FATTACCINI, CM
    HAMON, M
    [J]. JOURNAL OF NEUROCHEMISTRY, 1993, 60 (06) : 2059 - 2067