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At least 19 recordsLinked to original sources
PubMed2003

The crystal structures of the chiral alkyllithium bases [n-BuLi.(-)-sparteine]2 and [Et2O.(i-PrLi)2.(-)-sparteine].

The crystal structures of the two chiral alkyllithium bases [n-BuLi.(-)-sparteine]2 (1) and [Et2O.(i-PrLi)2.(-)-sparteine] (2) have been determined. For compound 1, a symmetric dimer is observed in the solid state, with two (-)-sparteine ligands coordinating to the lithium centers. Because of steric reasons, compound 2 crystallizes as an unsymmetric dimer with the four methyl groups pointing away from the sterically demanding (-)-sparteine ligand. Compound 2 contains one four-coordinate lithium center [coordinated to (-)-sparteine] and one three-coordinate lithium center (coordinated to Et2O). As a result of this arrangement, significantly different Li-C distances are found in the central four-membered ring of compound 2.

Journal Article↗
PubMed1989

Sparteine oxidation polymorphism: phenotyping by measurement of sparteine and its dehydrometabolites in plasma.

Phenotyping of the ability to oxidize sparteine was markedly facilitated by analyzing sparteine and dehydrosparteines in a single plasma sample by gas chromatography. The definitive identification of extensive and poor metabolizers was possible only 90 min after ingestion of 100 mg sparteine sulphate. In 121 healthy volunteers determination of the plasma level ratio was compared to the established determination of the metabolic ratio in urine. In each subject the alloted phenotype was the same by both methods. Plasma and urine analysis showed 9.9% of poor metabolizers.

Adult↗
PubMed2006

Crystal structures of the chiral lithiosilanes [(Lis)-PhMe2SiLi x THF x (-)-sparteine] and [Ph2(NEt2)SiLi x (-)-sparteine].

The (-)-sparteine-coordinated lithiosilanes (Lis)-4 and 5 crystallize as monomers with coordination numbers of 4 and 3 on lithium and represent the first structurally characterized enantiopure lithiosilanes. Both systems are also monomeric in solution with Si-Li contacts detected by 29Si-7Li couplings in the 29Si NMR spectrum (for 5 even at room temperature).

Journal Article↗
PubMed2003

Mechanistic investigations of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols using (-)-sparteine.

The mechanistic details of the Pd(II)/(-)-sparteine-catalyzed aerobic oxidative kinetic resolution of secondary alcohols were elucidated, and the origin of asymmetric induction was determined. Saturation kinetics were observed for rate dependence on [(-)-sparteine]. First-order rate dependencies were observed for both the Pd((-)-sparteine)Cl(2) concentration and the alcohol concentration at high and low [(-)-sparteine]. The oxidation rate was inhibited by addition of (-)-sparteine HCl. At low [(-)-sparteine], Pd-alkoxide formation is proposed to be rate limiting, while at high [(-)-sparteine], beta-hydride elimination is proposed to be rate determining. These conclusions are consistent with the measured kinetic isotope effect of k(H)/k(D) = 1.31 +/- 0.04 and a Hammett rho value of -1.41 +/- 0.15 at high [(-)-sparteine]. Calculated activation parameters agree with the change in the rate-limiting step by increasing [(-)-sparteine] with DeltaH(++) = 11.55 +/- 0.65 kcal/mol, DeltaS(++) = -24.5 +/- 2.0 eu at low [(-)-sparteine], and DeltaH(++) = 20.25 +/- 0.89 kcal/mol, DeltaS() = -5.4 +/- 2.7 eu at high [(-)-sparteine]. At high [(-)-sparteine], the selectivity is influenced by both a thermodynamic difference in the stability of the diastereomeric Pd-alkoxides formed and a kinetic beta-hydride elimination to maximize asymmetric induction. At low [(-)-sparteine], the selectivity is influenced by kinetic deprotonation, resulting in lower k(rel) values. A key, nonintuitive discovery is that (-)-sparteine plays a dual role in this oxidative kinetic resolution of secondary alcohols as a chiral ligand on palladium and as an exogenous chiral base.

Alcohols↗
PubMed1996

Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan.

OBJECTIVES: To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine. METHODS: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated. Patients and healthy control subjects were not selected on the basis of their CYP2D6 phenotypes. RESULTS: Chronic renal failure was associated with a decrease in sparteine partial metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to 670 ml/min in patients with renal failure versus median of 635 ml/min and range of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with renal failure. However, sparteine metabolic ratio was not significantly altered in patients with renal failure and showed that all patients were extensive metabolizers of sparteine. Although fractional urinary excretion of dextrorphan decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%) compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also showed that all subjects were extensive metabolizers of dextromethorphan. The amount of dextromethorphan excreted in urine correlated with creatinine clearance independently from CYP2D6 activity measured as sparteine partial metabolic clearance. However, it did not correlate with sparteine metabolic ratio or with fractional urinary excretion of dehydrosparteine. CONCLUSION: Assessment of CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive metabolizer patients with chronic renal failure. However, in these subjects, dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.

Administration, Oral↗
PubMed1995

Mechanism of cytochrome P450 2D6-catalyzed sparteine metabolism in humans.

Two different reaction mechanisms for the formation of the two human enamine-structured sparteine metabolites by cytochrome P450 2D6 have been discussed in the literature. These mechanisms are either initial one-electron oxidation of N1 of sparteine followed by deprotonation of the aminium radical cation, resulting in the formation of different carbon radicals and oxygen rebound of the carbon radicals, or oxidation of the carbon atoms adjacent to N1 by the enzyme, directly producing the respective carbon radicals. With a spectrum of deuterium-labeled isotopomers of sparteine, stereoselectivity and kinetic isotope effects of human sparteine metabolism were investigated by in vitro and in vivo experiments and were compared with chemical oxidation of 17-oxosparteine. These experiments revealed that the major human sparteine metabolite 2,3-didehydrosparteine is formed via highly stereoselective abstraction of the 2 beta-hydrogen atom; the deuterium label was completely retained during metabolism when 2R-[2H]sparteine was used as substrate. Chemical oxidation of 17-oxosparteine by Ce4+, as a model for one-electron oxidation of N1 of a sparteine-like structure, resulted in the sole formation of the 5,6-unsaturated enamine, and no 2,3-unsaturated enamine, structurally equivalent to the human major metabolite, was found. An unequivocal discrimination between the two possible reaction mechanisms was not possible by simple interpretation of the magnitude of the kinetic deuterium isotope effects. However, results of competitive and noncompetitive experiments revealed the presence of a nondissociative enzymatic mechanism for the formation of the two sparteine metabolites, i.e., the sparteine molecule that is bound to the substrate binding site of cytochrome P450 2D6 performs orientational changes without dissociating from the activated enzyme/substrate complex before the product-determining first irreversible reaction step. These results agree with the hypothesis that sparteine metabolism proceeds by direct carbon oxidation. Because electron transfer from amines to P450 may occur over some distance, the possibility of a sequential electron-proton transfer reaction during sparteine metabolism cannot be ruled out completely as an alternative reaction mechanism for sparteine metabolism.

Binding, Competitive↗
PubMed1985

Sparteine increases insulin release by decreasing the K+ permeability of the B-cell membrane.

The effects of sparteine on the pancreatic B-cell function have been studied with mouse islets. In the presence of a non-stimulatory concentration of glucose (3 mM), sparteine (0.2-1 mM) decreased the rate of 86Rb+ efflux from islet cells, depolarized the B-cell membrane, induced a glucose-like electrical activity and stimulated insulin release. This increase in release was observed over a large range of glucose concentrations (3-20 mM), and was most marked in the presence of 10 mM glucose. At this concentration of glucose, the effect of sparteine was already detected with 0.02 mM and was maximal with 0.5 mM. Higher concentrations of sparteine only had a transient effect on insulin release. In the presence of 10 mM glucose, 0.2 mM sparteine decreased 86Rb+ efflux and increased 45Ca2+ efflux from islet cells. The effect on 86Rb+ efflux was only transient in the presence of extracellular calcium, whereas the effect on 45Ca2+ efflux required the presence of extracellular calcium. The electrical activity induced by glucose in B-cells was augmented by sparteine which, at a concentration of 0.5 mM, produced a persistent depolarization with continuous spike activity. The potentiation of insulin release by sparteine was not reversible, but was inhibited by adrenaline and completely blocked by omission of extracellular calcium. Sparteine reversed the increase in 86Rb+ efflux and the decrease in insulin release caused by diazoxide. These results show that sparteine increases insulin release by reducing the K+-permeability of the B-cell membrane.

Animals↗
PubMed1993

Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Citalopram↗
PubMed1991

Effect of (+)-sparteine on nicotinic acetylcholine receptors in the neurons of rat superior cervical ganglion.

The effects of (+)-sparteine, a ganglionic blocking agent, on acetylcholine (ACh)-induced membrane currents and on fast excitatory postsynaptic currents (EPSCs) were studied in the neurons of rat isolated superior cervical ganglion, with the whole-cell patch-clamp recording method and the two-electrode voltage-clamp method, respectively. (+)-Sparteine (2 microM) reduced the ACh-induced current caused by activation of nicotinic ACh receptors (AChRs) in a voltage-independent manner at membrane potentials of -50 mV to +30 mV, whereas its blocking effect increased at more negative membrane potentials. The dose-response relationship for ACh was modified by 2 microM (+)-sparteine at -50 mV and at -90 mV in a fashion typical for competitive rather than noncompetitive antagonists. The apparent mean open time of the AChR channel, as estimated from the power density spectrum of the ACh-induced current fluctuations at -90 mV, was not decreased by 2 microM (+)-sparteine, in contrast to what was observed with hexamethonium, the well known open-channel blocker for ganglionic AChRs. At higher concentrations, i.e., 5 microM and 10 microM (lower concentrations were not effective), (+)-sparteine reduced the amplitude of the EPSC and the time constant of the EPSC decay. The former effect was voltage independent, whereas the latter effect was voltage independent at membrane potentials of -70 mV and more positive and increased at membrane potentials of -90 and -110 mV. These results suggest that (+)-sparteine produces in ganglionic AChRs a competitive blocking effect and, in addition, an open-channel blockade. The latter component probably provides a smaller contribution than does the former to the blockade by (+)-sparteine of the ACh-induced current. Conformational analysis of the (+)-sparteine molecule was performed, and the dimensions of the molecule were measured. Minimum dimensions of the space-filling profile for two conformers, high and low populated, were found to be 7.3 x 7.9 A and 6.8 x 7.5 A, respectively. Both profiles are larger than the channel profile at which the open-channel blockers have been suggested to bind, which may explain comparatively low open-channel-blocking activity of (+)-sparteine.

Acetylcholine↗
PubMed1992

The relationship between paroxetine and the sparteine oxidation polymorphism.

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol.hr/L), whereas at steady state the median AUCss tau interphenotype difference was only twofold (4410 versus 2550 nmol.hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/dehydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

Adult↗