Functional diversity among 5-substituted nicotine analogs; in vitro and in vivo investigations

被引:15
作者
Dukat, M
Damaj, IM
Young, R
Vann, R
Collins, AC
Marks, MJ
Martin, BR
Glennon, RA
机构
[1] Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Sch Med, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA
[3] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA
关键词
nicotinic receptor; (-)-nicotine; 5-bromonicotine; 5-methoxynicotine; in vitro model; in vivo model;
D O I
10.1016/S0014-2999(01)01570-9
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Two 5-substituted derivatives of nicotine (nicotinic acetylcholine receptor: K-i = 2.4 nM) were synthesized and evaluated: 5-bromonicotine (K-i = 6.9 nM) and 5-methoxynicotine (K-i = 14.3 nM). Despite their high affinity, neither 5-bromonicotine nor 5-methoxynicotine mimicked nicotine in producing antinociceptive (tail-flick, hotplate), hypolocomotor, or hypothermic effects in mice. Neither agent antagonized the hypolocomotor actions of nicotine, whereas 5-methoxynicotine, but not 5-bromonicotine, antagonized the antinociceptive (tail-flick) activity of nicotine in a dose-related manner. In tests of stimulus generalization using rats trained to discriminate 0.6 mg/ka of ( -)-nicotine from vehicle, 5-bromonicotine substituted for nicotine. Further evaluation of 5-bromonicotine indicated that it might be a partial agonist at alpha4beta2 receptors (stimulation of Rb- efflux; alpha4beta2 receptors expressed in oocytes) and at alpha3-containing nicotinic acetylcholine receptors (synaptosomal dopamine release). Thus, 5-bromonicotine might be acting as a partial agonist at alpha4beta2 receptors and/or some of its effects might be related to interactions with non-alpha4beta2 receptors. Clearly, the effects of 5-bromonicotine and 5-methoxynicotine are different from those of nicotine, and from one another. These actions demonstrate that substitution at the 5-position of nicotine exerts a profound influence on the pharmacological profile as well as agonist/antagonist properties of nicotine. (C) 2002 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:171 / 180
页数:10
相关论文
共 39 条
  • [11] Pyrrolidine-modified and 6-substituted analogs of nicotine: A structure-affinity investigation
    Dukat, M
    Fiedler, W
    Dumas, D
    Damaj, I
    Martin, BR
    Rosecrans, JA
    James, JR
    Glennon, RA
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1996, 31 (11) : 875 - 888
  • [12] Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic ligands
    Dukat, M
    Dowd, M
    Damaj, MI
    Martin, B
    El-Zahabi, MA
    Glennon, RA
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1999, 34 (01) : 31 - 40
  • [13] EDDY NB, 1953, J PHARMACOL EXP THER, V107, P385
  • [14] Finney D.J., 1952, Statistical method in biological assay
  • [15] GLENNON AR, 2000, PHARM ACTA HELV, V74, P103
  • [16] CHARACTERIZATION OF NICOTINIC RECEPTOR-MEDIATED [H-3] DOPAMINE RELEASE FROM SYNAPTOSOMES PREPARED FROM MOUSE STRIATUM
    GRADY, S
    MARKS, MJ
    WONNACOTT, S
    COLLINS, AC
    [J]. JOURNAL OF NEUROCHEMISTRY, 1992, 59 (03) : 848 - 856
  • [17] Neuronal nicotinic acetylcholine receptors as targets for drug discovery
    Holladay, MW
    Dart, MJ
    Lynch, JK
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (26) : 4169 - 4194
  • [18] INTRATHECAL MORPHINE IN MICE - A NEW TECHNIQUE
    HYLDEN, JLK
    WILCOX, GL
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1980, 67 (2-3) : 313 - 316
  • [19] RESOLUTION OF (+1)-5-BROMONORNICOTINE - SYNTHESIS OF (R)-NORNICOTINE AND (S)-NORNICOTINE OF HIGH ENANTIOMERIC PURITY
    JACOB, P
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1982, 47 (21) : 4165 - 4167
  • [20] ABERRANT SYNTHESIS IN HIGHER PLANTS .1. FORMATION OF 5-FLUORONICOTINE FROM 5-FLUORONICOTINIC ACID IN NICOTIANA-TABACUM
    LEETE, E
    BODEM, GB
    MANUEL, MF
    [J]. PHYTOCHEMISTRY, 1971, 10 (11) : 2687 - &