Oxaprotiline: enantioselective noradrenaline uptake inhibition indicated by intravenous amine pressor tests but not α2-adrenoceptor binding to intact platelets in man
- 12 Downloads
The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (−) oxaprotiline CGP 12 103 A (levoprotiline) and the S (+) oxaprotiline CGP 12 104 A, have been used as tools for a methodological Phase I study.
Only the S (+) enantiomer CGP 12 104 A inhibits noradrenaline uptake.
Intravenous amine pressor tests and ex vivo measurement of α2-adrenoceptor binding to intact human platelets were compared with respect to their reliability in indicating CGP 12 104 A-induced amine uptake inhibition and possibly associated α2-receptor down-regulation in healthy subjects.
α2-Adrenoceptor binding on intact human platelets did not distinguish between CGP 12 104 A and CGP 12 103 A.
However, amine pressor tests reflected the amine uptake inhibiting effect of CGP 12 104 A as a 5-fold decrease in tyramine pressor sensivity and a 5-fold increase in noradrenaline pressor sensitivity.
Key wordsOxaprotiline Levoprotiline noradrenaline uptake inhibitors enantiomers CGP 12 103 A CGP 12 104 A amine pressor tests α2-adrenoceptor binding intact human platelets
Unable to display preview. Download preview PDF.
- 1.Freyschuss U, Sjöqvist F, Tuck D (1970) Tyramine pressor effects in man before and during treatment with nortriptyline or ECT: correlation between plasma level and effect of nortriptyline. Pharmacol Clin 2: 72–78Google Scholar
- 2.Ghose K, Gifford LA, Turner P, Leighton M (1976) Studies of the interaction of desmethylimipramine with tyramine in man after a single oral dose, and its correlation with the plasma concentration. Br J Clin Pharmacol 3: 334–337Google Scholar
- 3.Ghose K (1980) Biochemical assessment of antidepressive drugs. Br J Clin Pharmacol 10: 539–550Google Scholar
- 4.Ghose K (1980) Sympathomimetic amines and tricyclic anti-depressant drugs. Neuropharmacol 19: 1251–1254Google Scholar
- 5.Ghose K (1984) Tyramine pressor test: implications and limitations. Meth Find Exptl Clin Pharmacol 6: 455–464Google Scholar
- 6.Jedrychowski M, Hoffmann E, Bieck PR (1989) A rapid and sensitive method for the quantitation of levoprotiline in human blood and plasma. J Pharm Biomed Analysis 7: 1897–1901Google Scholar
- 7.Motulsky HJ, Insel PA (1982) Adrenergic receptors in man: direct identification, physiologic regulation, and clinical alteration. N Engl J Med 307: 18–29Google Scholar
- 8.Reimann IW, britzelmeier C, Bieck PR (1987) Intrasubject variability of platelet α2-adrenoceptor binding sites in healthy volunteers. Meth Find Exptl Clin Pharmacol 9: 677–683Google Scholar
- 9.Reimann IW, Firkusny L, Antonin KH, Bieck PR (1992) Intravenous amine pressor tests in healthy volunteers. Within- and between subject variances and sex differences. Eur J Clin Pharmacol 42: 137–141Google Scholar
- 10.Siwers B, Freyschuss U, Hamberger B, Tuck D, Malmfors T, Sjöqvist F (1970) A quantitative approach to the initial clinical trial of tricyclic antidepressants: a comparison of Leo 640 and nortriptyline. Eur J Clin Pharmacol 3: 12–17Google Scholar
- 11.U'Prichard DC, Daiguji M, Tong C, Mitrius JC, Meltzer HY (1982) Alpha2-adrenergic receptors: Comparative biochemistry of neural and non-neural receptors, and in vivo analysis in psychiatric patients. In: Usdin E and Hanin E (Eds) Biological Markers in Psychiatry and Neurology. Pergamon Press, Oxford, pp. 205–217Google Scholar
- 12.Waldmeier P, Baumann P, Hauser K, Maitre L, Storni A (1982) Oxaprotiline, a noradrenaline uptake inhibitor with an active and inactive enantiomer. Biochem Pharmacol 31: 2169–2176Google Scholar
- 13.Wood K, Coppen A (1982) Psychiatry and platelets. In: Progress in Pharmacology, Vol. 4/4. Gustav Fischer Verlag. Stuttgart/New York, pp. 147–162Google Scholar