Summary
Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxyN-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3 H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured.
The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors.
Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models. Because of the in vivo formation of N-0437 after N-0724 and N-0953 administration, it is hypothesized that this dopaminergic activity is the result of metabolic activation. The cyclopentoxy group (present in N-0953) then appears to be an interesting prodrug moiety because it seems to give rise to small (but sufficient) and constant N-0437 levels in the brain.
Deceased January 2, 1990
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References
Arneric SP, Long JP, Williams M, Goodale DB, Mott J, Lakoski JM, Gebhart GF (1983) RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane): central effects of a new dopamine receptor agonist. J Pharmacol Exp Ther 224:161–170
Beart PM, Cook CJ, Cincotta M, De Vries DJ, Tepper P, Dijkstra D, Horn AS (1987) Radioreceptor binding reveals the potencies of N,N-disubstituted 2-aminotetralins as D2 dopamine agonists. Naunyn-Schmiedeberg's Arch Pharmacol 336:487–493
Beaulieu M, Itoh Y, Tepper P, Horn AS, Kebabian JW (1984) N,N-Disubstituted 2-aminotetralins are potent D-2 dopamine receptor agonists. Eur J Pharmacol 105:15–21
Broly F, Libersa C, Lhermitte M, Bechtel P, Dupuis B (1989) Effect of quinidine on the dextromethorphan O-demethylase activity of microsomal fractions from human liver. Br J Clin Pharmacol 28:29–36
Cho AK, Hodshon BJ, Lindeke B, Jonsson J (1975) The-p-hydroxylation of amphetamine and phentermine by rat liver microsomes. Xenobiotica 5:531–538
Costall B, Naylor RJ, Cannon JG, Lee T (1977) Differential activation by some 2-aminotetralin derivatives of the receptor mechanisms in the nucleus accumbens of rat which mediate hyperactivity and stereotyped biting. Eur J Pharmacol 41:307–319
De Jonge H (1964) Inleiding tot de medische statistiek, deel 2 klassieke methoden. (Introduction to medical statistics, part 2. Classical methods.) Verhandeling van het nederlands instituut voor praeventieve geneeskunde 2e druk, Leiden, pp 457–459, 688
Den Daas I, Rollema H, De Vries JB, Tepper PG, Horn AS (1989) Analysis of the dopamine agonist N-0437 in rat serum using reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr Biomed Appl 487:210–214
Den Daas I, Tepper PG, Horn AS (1990) Improvement of the oral bioavailability of the selective dopamine agonist N-0437 in rats: the in vitro and in vivo activity of eight ester prodrugs. Naunyn-Schmiedeberg's Arch Pharmacol 341:186–191
Fuller RW, Baker JC, Molloy BB (1977) Biological disposition of rigid analogs of amphetamine. J Pharm Sci 66:271–272
Gerding TK, Drenth BFH, Roosenstein HJ, De Zeeuw RA, Tepper PG, Horn AS (1990a) The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration: 1. Disposition and metabolic profiling. Xenobiotica 20:515–524
Gerding TK, Drenth BFH, De Zeeuw RA, Tepper PG, Horn AS (1990b) The metabolic fate of the dopamine agonist 2-(N-pro-pyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration: 2. Isolation and identification of metabolites. Xenobiotica 20:525–536
Giannina T, Meli A (1969) Prolonged oestrogenic activity in rats after single oral administration of ethinyloestradiol-3-cyclopentyl ether. J Pharm Pharmacol 21:271–272
Hacksell U, Svensson U, Nilsson JLG, Hjorth S, Carlsson A, Wikström H, Lindberg P, Sanchez D (1979) N-Alkylated 2-aminotetralins: central dopamine-receptor stimulating activity. J Med Chem 22:1469–1475
Imperato A, Di Chiara G (1984) Trans-striatal dialysis coupled to reverse phase high performance liquid chromatography with electrochemical detection: a new method for the study of the in vivo release of endogenous dopamine and metabolites. J Neurosci 4:966–977
Imperato A, Tanda G, Frau R, Di Chiara G (1988) Pharmacological profile of dopamine receptor agonists as studied by brain dialysis in behaving rats. J Pharmacol Exp Ther 245:257–264
König JFR, Klippel RA (1963) The rat brain: a stereotaxic atlas of the forebrain and lower parts of the brainstem. Williams and Wilkins, Baltimore
Liebman JM, Gerber R, Hall NR, Altar CA (1988) Heterogeneous rotational responsiveness in 6-hydroxydopamine-denervated rats: pharmacological and neurochemical characterization. Psychopharmacology 96:477–483
Marquardt GM, DiStefano V (1975) The hepatic microsomal metabolism of β-3,4-methylenedioxyamphetamine (MDA). Life Sci 15:1603–1610
Meli A, Steinetz BG, Beach VL, Wolff A, Giannina T (1965) Biological and chromatographic evidence for the storage of ethynylestradiol-3-cyclopentyl ether in rat brain. Proc Soc Exp Biol Med 119:602–606
Mulder TBA, Grol CJ, Dijkstra D, Horn AS (1985) Kinetic and pharmacological profiles of the in vitro binding of the potent dopamine agonist (3H)N,N-dipropyl-5,6-dihydroxy-2-amino tetralin to rat striatal membranes. Eur J Pharmacol 112:73–79
Rouillard C, Bedard PJ (1988) Specific D1 and D2 dopamine agonists have synergistic effects in the 6-hydroxydopamine circling model in the rat. Neuropharmacology 27:1257–1264
Roy SD (1990) Kinetics of in vitro metabolism of methoxyphenamine in rats. Xenobiotica 20:55–70
Rusterholz DB, Long JP, Flynn JR, Cannon JG, Lee T, Pease JP, Clemens JA, Wong DT, Bymaster FB (1979) Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine. Eur J Pharmacol 55:73–82
Seeman P, Watanabe M, Grigoriadis D, Tedesco JL, George SR, Svensson U, Nilsson JLG, Neumeyer JL (1985) Dopamine D2 receptor binding sites for agonists, a tetrahedral model. Mol Pharmacol 28:391–399
Svensson K, Hjorth S, Clark D, Carlsson A, Wikström H, Andersson B, Sanchez D, Johansson AM, Arvidsson LE, Hacksell U, Nilsson JLG (1986) (+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors. J Neural Transm 65:1–27
Swart PJ, Drenth BFH, De Zeeuw RA (1990) A reversed-phase liquid chromatographic method with amperometric detection for the determination of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) in human plasma and urine. J Chromatogr Biomed Appl 528:464–472
Timmerman W, Westerink BHC, De Vries JB, Tepper PG, Horn AS (1989) Microdialysis and striatal dopamine release: stereoselective actions of the enantiomers of N-0437. Eur J Pharmacol 162:143–150
Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93
Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24:485–493
Van der Weide J, De Vries JB, Tepper PG, Horn AS (1986) Pharmacological profiles of three new, potent and selective dopamine receptor agonists: N-0434, N-0437 and N-0734. Eur J Pharmacol 125:273–282
Van der Weide J, De Vries JB, Tepper PG, Krause DN, Dubocovich ML, Horn AS (1988) N-0437: a selective D-2 dopamine receptor agonist in in vitro and in vivo models. Eur J Pharmacol 147:249–258
Westerink BHC, Tuinte MHJ (1986) Chronic use of intracerebral dialysis for the in vivo measurement of 3,4-dihydroxyphenylethylamine and its metabolite 3,4-dihydroxyphenylacetic acid. J Neurochem 46:181–185
Westerink BHC, Damsma G, Rollema H, De Vries JB, Horn AS (1987) Scope and limitations of in vivo brain dialysis: a comparison of its application to various neurotransmitter systems. Life Sci 41:1763–1776
Williams KIH, Layne DS, Hobkirk R, Nilsen M, Blahey PR (1967) Metabolism of doubly labelled ethynylestradiol-3-cyclopentyl ether in women. Steroids 9:275–287
Woodruff GN, Watling KJ, Andrews CD, Peat JA, McDermed JD (1977) Dopamine receptors in rat striatum and nucleus accumbens; conformational studies using rigid analogues of dopamine. J Pharm Pharmacol 29:422–427
Zweig JS, Castagnoli N Jr (1977) In vitro O-demethylation of the psychotomimetic amine. 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. J Med Chem 20:414–421
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Part of this work was presented at a satellite meeting of the XIth international congress of pharmacology: Dopamine '90 in Como, Italy (July 1990).
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Jansen, J.M., den Daas, I., Rollema, H. et al. Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437. Naunyn-Schmiedeberg's Arch Pharmacol 343, 134–142 (1991). https://doi.org/10.1007/BF00168600
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DOI: https://doi.org/10.1007/BF00168600