Summary1. M&B 9302, E-250, NSD 2023, and Lilly 51641, substrate-selective inhibitors of monoamine oxidase (MAO), and two non-selective inhibitors of MAO (tranylcypromine and phenelzine) have been compared in the rat for activity in (i) inhibiting rat brain monoamine oxidase in vitro and in vivo using tyramine, 5-hydroxytryptamine (5-HT) and benzylamine as substrates; (ii) increasing brain levels of noradrenaline (NA) and 5-HT and (iii) antagonizing tetrabenazine-induced sedation. 2. Concentrations of M&B 9302 and Lilly 51641 required to produce 50% inhibition of 5-HT oxidation by brain mitochondrial MAO were 1-4 x 10-8M and 2 5 x 10-7M respectively. Higher concentrations were required to inhibit tyramine oxidation whilst benzylamine oxidation was inhibited only at concentrations above 10-5M. 3. E-250 showed the reverse substrate-selectivity in inhibiting the oxidation of benzylamine at concentrations below that required to inhibit the oxidation of 5-HT. NSD 2023 showed little substrate selectivity in vitro. 4. Qualitatively similar results were obtained in vivo, except that NSD 2023 showed more marked substrate-selectivity. 5. All the inhibitors except E-250 produced a dose-related rise in brain 5-HT levels. Only phenelzine and Lilly 51641 showed a linear relationship between NA levels and dose. 6. All the drugs antagonized, in dose-related fashion, the effects of tetrabenazine in reducing locomotor activity. E-250 and NSD 2023 failed to restore locomotor activity to control levels whilst in high doses the other inhibitors, when given before tetrabenazine, produced a considerable increase in locomotor activity. 7. Antagonism of tetrabenazine sedation appears to be correlated with (a) inhibition of the enzyme species that oxidize 5-HT and NA but not with inhibition of the enzyme species that oxidize benzylamine; (b) the rise in brain 5-HT levels rather than NA levels.
The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.
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