- Metabolic disposition of tacrine in primary suspensions of rat hepatocyte and in single-pass perfused liver: In vitro/in vivo comparisons
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1. Incubations of tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate, THA) with a primary suspension of rat hepatocytes for 2 min resulted in formation of the 1-hydroxy derivative as the major metabolite with smaller amounts of the 2- and 4-hydroxy metabolites. 2. Apparent V(max) and K(m) for THA metabolism were 12.4 ± 3.3 nmol/min/g liver and 0.98 ± 0.34 μM respectively. 3. Incubations of THA for longer time-periods (> 10 min) resulted in irreversible binding of THA-derived radioactivity to hepatocellular protein. The apparent maximal rate of irreversible binding (B(max)) was 76.7 ± 30.5 pmol equivalents bound/h/mg cell protein, whereas the apparent K(b) for binding was 2.8 ± 1.4 μM. 4. The kinetic parameters, V(max) and K(m), were used to predict steady-state extraction ratios (ER(SS)) for various THA input concentrations (C(in)) in single-pass perfused rat liver. At low input concentrations (0.72-0.85 μM; C(in) K(m)), ER(SS) of THA was approximately 1. For higher C(in) (14.05, 20.72, 20.88 μM; C(in) ≥ K(m)), the calculated ER(SS) was markedly decreased with 0.300, 0.296 and 0.261, respectively. 5. The intrinsic clearance of THA (Cl(i)) estimated from in vitro hepatocyte data was 6.7 ml/min/g liver while the apparent oral THA clearance (Cl(oral)) calculated from in vivo rat data was 6.6 ml/min/g liver.
- Kukan,Bezek,Pool,Woolf
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- Simultaneous determination of tacrine and 1-hydroxy-, 2-hydroxy-, and 4- hydroxytacrine in human plasma by high-performance liquid chromatography with fluorescence detection
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An analytical method was developed for the simultaneous reversed-phase (cyano) high-performance liquid chromatographic determination with fluorescence detection of tacrine and 1-hydroxy-, 2-hydroxy-, and 4- hydroxytacrine in human plasma. Alkalinized human plasma samples were extracted with a mixture of chloroform/l-propanol (90:10, v/v). Extraction recoveries generally ranged from 68% to 83% for all four compounds and did not appear to be concentration dependent over the range examined. Calibration curves were constructed over the following ranges: 0.5-30.0 ng/mL for tacrine (THA) and 4-hydroxytacrine (4-OH-THA), 1.0-30.0 ng/mL for 2-hydroxytacrine (2-OH-THA), and 0.925-46.2 ng/mL for 1-hydroxytacrine (1-OH-THA). The intra- and interassay precision (RSD) for the quality control specimens analyzed during validation were ≤11.8% and ≤9.28%, respectively. The intra- and interassay accuracy (RE) for the quality control specimens analyzed during validation ranged from 14.1% to -7.5% and 12.1% to -3.33%, respectively, for all four compounds. The limit of quantitation was estimated as the level of the lowest concentration in the calibration curve for each compound based on acceptable interassay precision and accuracy statistics generated at this concentration. The sensitivity of the method was adequate for the determination of THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA following oral administration of Cognex (40 mg single dose) to normal volunteers.
- Haughey,McNaney,Collis,Brown,Siedlik,Balogh,Klockowski
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- Use of 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds for the treatment of aids
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There is disclosed the use of 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds of the formula below, where Xis hydrogen, loweralkyl or halogen; and Ris hydrogen, loweralkyl or benzyl; for the treatment of acquired immune deficiency syndrome (AIDS).
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- Method of reducing a carbonyl containing acridine
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A method of reducing a carbonyl containing acridine of the formula STR1 where n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, trifluoromethyl, or NR3 R4 where R3 and R4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl and R1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl, is disclosed.
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- 9-Amino-1,2,3,4-tetrahydroacridin-1-ols: Synthesis and evaluation as potential Alzheimer's disease therapeutics
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The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease - the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (±)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (±)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 μM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.
- Shutske,Pierrat,Kapples,Cornfeldt,Szewczak,Huger,Bores,Haroutunian,Davis
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p. 1805 - 1813
(2007/10/02)
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- 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds
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There are disclosed compounds having the formula STR1 wherein n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, NHCOR2 where R2 is loweralkyl, or NR3 R4 where R3 and R4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl; R1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl; Y is C=O or CR5 OH where R5 is hydrogen or loweralkyl; Z is CH2 or C=CR6 R7 where R6 and R7 are independently hydrogen or loweralkyl; or Y and Z taken together is CR5 =CH where CR5 and CH correspond to Y and Z respectively; an optical antipode thereof, or a pharmaceutically acceptable acid addition salt thereof, which are useful for enhancing memory, methods for synthesizing them, and pharmaceutical compositions comprising an effective memory enhancing amount of such a compound.
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- 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds
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There are disclosed compounds having the formula STR1 wherein X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, nitro, NHCOR2 wherein R2 is loweralkyl, or a group of the formula NR3 R4 wherein R3/s
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