EFFECTS OF ISOQUINOLINE DERIVATIVES STRUCTURALLY RELATED TO 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) ON MITOCHONDRIAL RESPIRATION

Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP(+))-li ke activity as inhibitors of complex I and alpha-ketoglutarate dehydro genase activity in rat brain mitochondrial fragments. We now examine t he ability of 19 isoquinoline derivatives and MPP(+) to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited res piration supported by either succinate + rotenone or tetramethylparaph enylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 isoquinoline derivatives and MPP(+) inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manne r. None of the isoquinoline derivatives were more potent than MPP(+). 6,7-Dimethoxy-1-styryl-3,4-dihydroisoquinoline uncoupled mitochondrial respiration. Qualitative structure activity relationship studies reve aled that isoquinolinium cations were more active than isoquinolines i n inhibiting mitochondrial respiration; these, in turn, were more acti ve than dihydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines. Thre e-dimensional quantitative structure activity relationship studies usi ng Comparative Molecular Field Analysis showed that the inhibitory; po tency of isoquinoline derivatives was determined by steric, rather tha n electrostatic, properties of the compounds. A hypothetical binding s ite was identified that may be related to a rate limiting transport pr ocess, rather than to enzyme inhibition. In conclusion, isoquinoline d erivatives are less potent in inhibiting respiration in intact mitocho ndria than impairing complex I activity in mitochondrial fragments. Th is suggests that isoquinoline derivatives are not accumulated by mitoc hondria as avidly as MPP(+). The activity of charged and neutral isoqu inoline derivatives implicates both active and passive processes by wh ich these compounds enter mitochondria, although the quaternary nitrog en moiety of the isoquinolinium cations favours mitochondrial accumula tion and inhibition of respiration. These findings suggest that isoqui noline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP(+).