NONNEUROTOXIC TETRALIN AND INDAN ANALOGS OF 3,4-(METHYLENEDIOXY)AMPHETAMINE (MDA)

被引:83
作者
NICHOLS, DE [1 ]
BREWSTER, WK [1 ]
JOHNSON, MP [1 ]
OBERLENDER, R [1 ]
RIGGS, RM [1 ]
机构
[1] PURDUE UNIV,SCH PHARM & PHARMACEUT SCI,DEPT PHARMACOL & TOXICOL,W LAFAYETTE,IN 47907
关键词
D O I
10.1021/jm00164a037
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methy-lenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (±)-MDMA-HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H] paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:703 / 710
页数:8
相关论文
共 43 条
[1]   MDMA-INDUCED NEUROTOXICITY - PARAMETERS OF DEGENERATION AND RECOVERY OF BRAIN-SEROTONIN NEURONS [J].
BATTAGLIA, G ;
YEH, SY ;
DESOUZA, EB .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1988, 29 (02) :269-274
[2]  
BATTAGLIA G, 1987, J PHARMACOL EXP THER, V242, P911
[3]   BEHAVIORAL-EFFECTS OF N-ETHYL-3,4-METHYLENEDIOXYAMPHETAMINE (MDE - EVE) [J].
BOJA, JW ;
SCHECHTER, MD .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1987, 28 (02) :153-156
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]   ANTIHYPERTENSIVE AMINOTETRALINS RELATED TO LABETALOL AND MEDROXALOL [J].
CLARK, RD ;
CAROON, JM ;
REPKE, DB ;
STROSBERG, AM ;
WHITING, RL ;
BROWN, CM .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1986, 75 (01) :80-82
[6]  
COLPAERT FC, 1982, J PHARMACOL EXP THER, V221, P206
[7]  
DEBOER TJ, 1963, ORG SYNTH, V4, P250
[8]  
DRAN R, 1967, B SOC CHIM FR, P4469
[9]   DISCRIMINATIVE STIMULUS PROPERTIES OF (+/-)-3,4-METHYLENEDIOXYMETHAMPHETAMINE AND (+/-)-3,4-METHYLENEDIOXYAMPHETAMINE IN PIGEONS [J].
EVANS, SM ;
JOHANSON, CE .
DRUG AND ALCOHOL DEPENDENCE, 1986, 18 (02) :159-164
[10]   COMPARISON OF EFFECTS OF 6-CHLORO-2-AMINOTETRALIN AND OF ORG-6582, A RELATED CHLOROAMPHETAMINE ANALOG, ON BRAIN-SEROTONIN METABOLISM IN RATS [J].
FULLER, RW ;
WONG, DT ;
SNODDY, HD ;
BYMASTER, FP .
BIOCHEMICAL PHARMACOLOGY, 1977, 26 (14) :1333-1337