Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B

Abstract

Sixteen analogs of N-methyl-1,2,3,6-tetrahydropyridine (MPTP) of varying degrees of flexibility have been studied as substrates of highly purified monoamine oxidases (MAO) A and B. The relative effectiveness of the various tetrahydropyridines as substrates of MAO A and B were evaluated in terms of the function turnover number/Km, as determined by initial rate measurements. The insertion of a methylene bridge between the phenyl and tetrahydropyridine moieties of MPTP to yield N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, rendering the molecule more flexible, greatly enhances reactivity with MAO B, but not with MAO A, as compared with MPTP itself, in accord with data in the literature (Youngster et al., 1989a). The ethylene-bridged MPTP analog, on the other hand, is a far better substrate of both forms of MAO than is MPTP itself. The effect of molecular flexibility on the rate of oxidation of these compounds is obscured by substituents on the aromatic ring. Branching and rigidity were detrimental to the activity as substrates of both forms of MAO. Those analogs of 1 which contain small electron-withdrawing substituents in the phenyl ring were found to be more selective for MAO B, while those substituted with bulky groups were selectively oxidized by MAO A. The substrate binding site of MAO A probably contains a lipophilic pocket larger than that found in a similar site in MAO B.

Computer modelling of monoamine oxidases

“…Compari son of the molds has shown that it is larger in MAO A than in MAO B (Figs. 1c, 1d); the latter well corre sponded to the literature data [22,27,28].…”

“…1). This assumption was consistent with data from other laboratories [22,23]. This obser vation we later used to formulate an important requirement to the compounds employed for such kind of research: adequate modeling of the active site of MAO can be carried out only with the use of revers ible competitive inhibitors of MAO characterized by preferentially "rigid" (with limited conformational mobility) structure and a limited set of conformers.…”

Synthesis and Monoamine Oxidase B Catalyzed Oxidation of C-4 Heteroaromatic Substituted 1,2,3,6-Tetrahydropyridine Derivatives

“…H NMR (DMSO-d6) δ 9.5 (bs, 2H, HCl), 8.89 (d, J ) 5.8, 2H, ArH), 8.07(d, J ) 6.0, 2H, ArH),6.94 (bs, 1H, NCH2CH), 3.94-4.15 (m, 2H, NCH2-CH), 3.33-3.66 (m, 2H, NCH2CH2), 2.42-2.46 (m, 2H, NCH2-CH2), 1.53-1.66 (m, 1H, NCH), 0.49-0.56 (m, 4H, NCHCH2). Anal.…”

Effect of a selective MAO-A inhibitor (Ro 41-1049) on striatal L-dopa and dopamine metabolism: An in vivo study

“…This is based on the fact that MAO-B but not MAO-A inhibitors protect against the neurotoxin MPTP which destroys dopamine nerve cells. However, there are MPTP analogs that are oxidized by MAO-A rather than MAO-B, making it equally likely that MAO-A inhibitors could play a protective role (Kindt et al, 1988;Kreuger et al, 1992).…”