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Selective inhibition by amiflamine of monoamine oxidase type A in rat brain, liver and duodenum

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Summary

Amiflamine (FLA 336(+)), N-desmethylamiflamine (FLA 788(+)) and N,N-didesmethylamiflamine (FLA 668(+)) were examined for their monoamine oxidase (MAO) inhibitory effects in rat brain, liver and duodenum and were compared with the irreversible inhibitors clorgyline and (-)-deprenyl. The potency of each FLA compound was the same in each tissue both in vitro and after oral administration with either serotonin or tyramine as substrate. The in vitro effect of FLA 788(+) was 2–6 times stronger than that of amiflamine although the compounds were equipotent after oral administration. FLA 668(+) was 2–3 times less potent than amiflamine in vitro and had very poor activity after oral administration. The deamination of phenethylamine was weakly afected by the three FLA compounds. Clorgyline inhibited strongly the deamination of serotonin and tyramine in the duodenum after oral administration, being 1,000 times more potent than in the brain and the liver. Similar results were obtained for (-)-deprenyl which, however, was more potent in inhibiting the deamination of phenethylamine than that of serotonin and tyramine. Amiflamine was a reversible MAO inhibitor with no MAO inhibitory capacity 24 h after a single oral dose. On the other hand the irreversible inhibitor clorgyline had a maximal effect on brain MAO 48 h after a single dose while the inhibitory effect in the duodenum had almost disappeared. The influence of amiflamine on the excretion of acid and basic metabolites of orally administered 14C-tyramine (58 μmol/kg) in rat was examined. Amiflamine, at doses that strongly inhibited MAO-A in rat brain, only slightly affected the excretion of 14C-labelled acid in urine during 6 and 24 h after the tyramine administration. The results in this study suggest that other factors than a low interaction with intestinal MAO may be of importance for the low tyramine potentiating effect obtained after oral administration of amiflamine.

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References

  • Ask A-L, Hellström W, Norrman S, Ögren S-O, Ross SB (1982a) Selective inhibition of the A form of monoamine oxidase by 4-dimethylamino-α-methylphenylalkylamine derivatives in the rat. Neuropharmacology 21:299–308

    Google Scholar 

  • Ask A-L, Högberg K, Schmidt L, Kiessling H, Ross SB (1982b) (+)-4-Dimethylamino-2,α-dimethylphenethylamine[FLA 336(+)], a selective inhibitor of the A form of monoamine oxidase in the rat brain. Biochem Pharmacol 31:1401–1406

    Google Scholar 

  • Ask A-L, Fagervall I, Ross SB (1983a) Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 324:79–87

    Google Scholar 

  • Ask A-L, Fagervall I, Ross SB (1983b) Selective inhibition by (+)-amphetamine of monoamine oxidase in catecholaminergic neurons in the rat brain. Prog Neur Psychopharmacol Biol Psych (Suppl) 22

  • Blackwell B (1963) Hypertensive crisis due to monoamine-oxidase inhibitors. Lancet II:849–851

    Google Scholar 

  • Campbell IC, Robinson DS, Lovenberg W, Murphy DL (1979) The effects of chronic regimens of clorgyline and pargyline on monoamine metabolism in the rat brain. J Neurochem 32:49–55

    Google Scholar 

  • Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, Shaw KM, Stern GM, Kumar P (1978) Deprenyl administration in man: a selective monoamine oxidase B inhibitor without the “cheese effect”. Psychopharmacology 57:33–38

    Google Scholar 

  • Finberg JPM, Tenne M, Youdim MBH (1981) Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type. Br J Pharmacol 73:65–74

    Google Scholar 

  • Fowler CJ, Oreland L (1982) Substrate- and stereoselective inhibition of human brain monoamine oxidase by 4-dimethylamino-α,2-methylphenethylamine (FLA 336). J Pharmacol 33:403–406

    Google Scholar 

  • Fowler CJ, Ross SB (1984) Selective inhibitors of monoamine oxidase-A and-B: biochemical, pharmacological and clinical properties. Med Res Rev (in press)

  • Garcha G, Imrie PR, Marley E, Thomas DV (1979) Effects of monoamine oxidase inhibitors (MAOI) pretreatment on the fate of intraduodenally instilled [14C]-tyramine. Br J Pharmacol 63:454P-455P

    Google Scholar 

  • Gershon MD (1982) Serotonergic neurotransmission in the gut. Scand J Gastroenteral (Suppl) 17 (71):27–41

    Google Scholar 

  • Goridis C, Neff NH (1971) Evidence for a specific monoamine oxidase associated with sympathetic nerves. Neuropharmacol 10:557–564

    Google Scholar 

  • Hall DWR, Logan BW, Parsons GH (1969) Further studies on the inhibition of monoamine oxidase by M & B 9302 (clorgyline). I. Substrate specificity in various mammalian species. Biochem Pharmacol 18:1447–1454

    Google Scholar 

  • Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17: 1285–1297

    Google Scholar 

  • Knoll J (1976) Analysis of the pharmacological effects of selective monoamine oxidase inhibitors. In: Wolstenholme GEW, Knight J (eds) Monoamine oxidase and its inhibition. Ciba Foundation Symposium 39. Elsevier, Exerpta Medica, North Amsterdam, Holland, pp 135–155

    Google Scholar 

  • Knoll J (1978) The possible mechanisms of action of (-)-deprenyl in Parkinson's disease. J Neur Transm 43:177–198

    Google Scholar 

  • Knoll J, Vizi ES, Somogyi G (1968) Phenylisopropylmethyl-propynylamine (E-250), a monoamineoxidase inhibitor antagonising the effects of tyramine. Arzneimittelforsch 18:109–112

    Google Scholar 

  • Knoll J, Magyar K (1972) Some puzzling pharmacological effects on monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5:393–408

    Google Scholar 

  • Lemberger L, Klutch A, Kuntzman R (1966) The metabolism of tyramine in rabbits. J Pharmacol Exp Ther 153:183–190

    Google Scholar 

  • Lipper S, Murphy DL, Slater S, Buchsbaum MS (1979) Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation. Psychopharmacology 62:123–128

    Google Scholar 

  • O'Carroll A-M, Fowler CJ, Phillips JP, Tobbia I, Tipton KF (1983) The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn-Schmiedeberg's Arch Pharmacol 322:198–202

    Google Scholar 

  • Ögren S-O, Ask A-L, Holm A-C, Florvall L, Lindbom L-O, Lundström J, Ross SB (1981) Biochemical and pharmacological properties of a new selective and reversible monoamine oxidase inhibitor, FLA 336(+). In: Youdim MBH, Paykel ES (eds) Monoamine oxidase — The state of the art. John Wiley and Sons, Chichester, pp 103–112

    Google Scholar 

  • Planz G, Quiring K, Palm D (1972) Rates of recovery of irreversibly inhibited monoamine oxidases: a measure of enzyme protein turnover. Naunyn-Schmiedeberg's Arch Pharmacol 273:27–42

    Google Scholar 

  • Ross SB, Renyi AL (1971) Uptake and metabolism of β-phenethylamine and tyramine in mouse brain and heart slices. J Pharm Pharmacol 23:276–279

    Google Scholar 

  • Squires RF (1972) Multiple forms of monoamine oxidase in intact mitochondria as characterized by selective inhibitors and thermal stability: a comparison of eight mammalian species. Adv Biochem Psychopharmacol 5:355–370

    Google Scholar 

  • Strolin Benedetti M, Boucher T, Carlsson A, Fowler CJ (1983a) Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat. Biochem Pharmacol 32:47–52

    Google Scholar 

  • Strolin Benedetti M, Dostert P, Guffroy C, Tipton KF (1983b) Partial or total protection from long-acting monoamine oxidase inhibitors (MAOIs) by new short-acting MAOIs of type A MD780515 and MD780236. In: Beckman H, Riederer P (eds) Monoamine oxidase and its selective inhibitors. Mod Probl Pharmacopsychiatr 19. Karger, Basel, pp 82–104

    Google Scholar 

  • Tacker M, McIsaac WM, Creaven PJ (1970) Metabolism of tyramine-1-14C by the rat. Biochem Pharmacol 19:2763–2773

    Google Scholar 

  • Waldmeier PC, Delini-Stula A, Maître L (1976) Preferential deamination of dopamine by an A type monoamine oxidase in rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 292:9–14

    Google Scholar 

  • Waldmeier PC, Felner AE, Maître L (1981) Long-term effects on selective MAO activity and amine metabolism. In: Youdim MBH, Paykel ES (eds) Monoamine oxidase — The state of the art. John Wiley and Sons Ltd, Chichester pp 103–112

    Google Scholar 

  • Wurtman RJ, Axelrod J (1963) A sensitive and specific assay for the estimation of monoamine oxidase. Biochem Pharmacol 12:1439–1441

    Google Scholar 

  • Yang H-YT, Neff NH (1973) β-Phenethylamine: a specific substrate for type B monoamine oxidase of brain. J Pharmacol Exp Ther 187:365–371

    Google Scholar 

  • Yang H-YT, Neff NH (1974) The monoamine oxidases of brain: Selective inhibition with drugs and consequences for the metabolism of the biogenic amines. J Pharmacol Exp Ther 189:733–740

    Google Scholar 

Download references

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  1. Research and Development Laboratories, Astra Läkemedel AB, S-15185, Södertälje, Sweden

    Anna-Lena Ask

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Ask, AL. Selective inhibition by amiflamine of monoamine oxidase type A in rat brain, liver and duodenum. Naunyn-Schmiedeberg's Arch. Pharmacol. 327, 56–63 (1984). https://doi.org/10.1007/BF00504992

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  • DOI: https://doi.org/10.1007/BF00504992

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