Structure-activity studies on amphetamine analogs using drug discrimination methodology

https://doi.org/10.1016/S0091-3057(84)80071-4Get rights and content

Animals (rats) trained to discriminate 1.0 mg/kg of S(+)-amphetamine sulfate from saline, using a standard operant training procedure, were administered doses of various amphetamine analogs in tests of stimulus generalization in order to study structure-activity relationships (SAR). The types of structural variation of the amphetamine molecule that were investigated included (a) benz-fusion of the aromatic nucleus, (b) α-demethylation of the alkyl side chain, (c) conversion of the benzylic methylene to a carbonyl group, and (d) conformational restriction of the side chain. Benz-fusion and α-demethylation appear to have a detrimental effect on activity in that none of these analogs produced amphetamine-appropriate responding. However, the carbonylated analog, i.e., cathinone, was found to be equipotent with amphetamine. Furthermore, as with amphetamine, the S-isomer of cathinone was found to be more active than its enantiomer. With respect to the conformationally-restricted analogs, the most potent compound was 2-aminotetralin which was about half as active as racemic amphetamine.

References (32)

  • K. Bailey et al.

    Proton magnetic resonance spectra of some amphetamines and related compounds and observations on rotomer populations

    Can J Chem

    (1971)
  • J.G. Cannon et al.

    Comparison of biological effects of N-alkylated congeners of β-phenethylamine derived from 2-aminotetralin, 2-aminoindan and 6-aminobenzocyclo-heptene

    J Med Chem

    (1980)
  • F.C. Colpaert et al.
  • G.D. D’Mello et al.

    Comparison of the discriminative stimulus properties of cocaine and amphetamine in rats

    Br J Pharmacol

    (1977)
  • R.P. Edkins et al.

    Halogen analogues of adrenaline and ephedrine

    Q J Pharm Pharmacol

    (1936)
  • G.D. Ewing et al.

    An efficient synthesis of 4,5-benzotropone from o-xylylene dibromide

    J Org Chem

    (1975)
  • Cited by (47)

    • Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats

      2016, European Neuropsychopharmacology
      Citation Excerpt :

      The present results are consistent with previous evidence for stereoselectivity in potency but not quality of pharmacological effects for cathinone. For example, previous studies found that both S(−) and R(+)cathinone promote DA release from rat brain striatal slices (Kalix, 1986) and substitute for S(+)amphetamine in rats trained to discriminate amphetamine from saline (Glennon et al., 1984), and in both of these studies, S(−)cathinone was more potent than R(+)cathinone. In addition, the present study found that both cathinone enantiomers facilitated ICSS, and drug-induced facilitation of ICSS is often interpreted as an abuse-related behavioral effect that correlates both with expression of drug reinforcement in preclinical assays of drug self-administration and with abuse potential in humans (Negus and Miller, 2014).

    • Alpha-ethyltryptamines as dual dopamine-serotonin releasers

      2014, Bioorganic and Medicinal Chemistry Letters
    • Synthetic cathinones: Chemical phylogeny, physiology, and neuropharmacology

      2014, Life Sciences
      Citation Excerpt :

      What we now know as cathinone was coincidentally shown to be a locomotor stimulant in 1962. Various other studies over the ensuing years concluded that, like amphetamine, cathinone and several related cathinone analogs are DA releasing agents (Kalix and Glennon, 1986; Glennon et al., 1987), that both optical isomers of cathinone substitute for training drug in rats trained to discriminate (+)amphetamine from vehicle, that stimulus generalization could be blocked by haloperidol (Glennon et al., 1984a), and that cathinone itself could be used as a training drug in drug discrimination studies using rats as subjects (Glennon et al., 1984a, 1984b; Schechter and Glennon, 1985). In these, and other, investigations S(−)cathinone was found more potent that R(+)cathinone just as S(+)amphetamine is more potent than R(−)amphetamine.

    • Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention

      2014, Advances in Pharmacology
      Citation Excerpt :

      S(−)Methcathinone, but not S(+)METH, substituted in (−)ephedrine-trained rats (Bondareva, Young, & Glennon, 2002). With racemic cathinone as the training drug, stimulus generalization occurred to both cathinone optical isomers (S > R), cathine, (+)AMPH, METH, and cocaine, but not to α-desmethylcathinone, 4-hydroxycathinone, 4-methoxycathinone, or 4-chlorocathinone (Glennon, Schechter, et al., 1984; Glennon, Young, et al., 1984; Schechter & Glennon, 1985), nor 4-fluorocathinone (unpublished data). Likewise, (+)AMPH, cocaine, cathine, but not α-desmethylcathinone, substituted in cathinone-trained rats (Goudie, Atkinson, & West, 1986).

    • Aminoindane Analogues

      2013, Novel Psychoactive Substances: Classification, Pharmacology and Toxicology
    View all citing articles on Scopus
    View full text