Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (−)S 20500

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT_1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT_1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock (conflict procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01–3.0 mg/kg) and (–) S 20500 (0.3–5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03–5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (–)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (–)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (–)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT_1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (–)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [³H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (–)S 20500 in displacing [³H]8-OH-DPAT (IC₅₀=2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT_1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.     

Effects of μ-, δ- and κ-opioid antagonists in atrial preparations from nonfailing and failing human hearts

• 1.1. We examined the effects of naloxone (preferentially μ-antagonist), naltrindole (selective δ-antagonist) or nor-binaltorphimine (nor-BNI, selective κ-antagonist) on auricular myocardium tissue from nonfailing and failing human hearts.
• 2.2. The opioid antagonists used in this study induced inhibitory effects in auricular strips from failing and nonfailing human hearts. In addition, the maximal effect, the IC₅₀, and the slope of concentration-response curves obtained with μ-, δ-, and κ-opioid antagonists were similar in failing and nonfailing human heart tissues.
• 3.3. The K-antagonist was more effective than naltrindole or naloxone. Moreover, the IC₅₀ for nor-BNI (0.25±0.01 × 10⁻⁵M) was lower than the IC₅₀ for naloxone (26.5±5.0 × 10⁻⁵M) and naltrindole (13.8±2.0 × 10⁻⁵M). Similar results were obtained in auricular strips from failing human hearts.
• 4.4. Our results demonstrate that the failing heart does not modify the inhibitory cardiac effects obtained with selective opioid antagonists.

     

Stereoselective inhibition of calmodulin-dependent cAMP phosphodiesterase from bovine heart by (+)- and (−)-nimodipine

Summary The inhibitory effects of racemic (±)-nimodipine and of optically pure (+)- and (–)-nimodipine on the basal and calmodulin-dependent activity of a cAMP phosphodiesterase from bovine heart were investigated. The inhibition by (±)-nimodipine could not be overcome by an excess of calmodulin. However, increase of the cAMP concentration in the assay from 2 × 10^–4 mol/l to 2 × 10^–2 mol/l caused a shift of the IC₅₀ for the inhibition by (±)-nimodipine from 2.8 × 10^–6 mol/l to 6 × 10^–5 mol/l. Dixon-plot analysis revealed an inhibitory constant of K _i = 2.3 mol/l, Experiments with the two enantiomers showed that (+)-nimodipine is by about one order of magnitude more potent than (–)-nimodipine. This contrasts with the stereoselectivity of the Ca²⁺ channel inhibitory activity on isolated rings of the rabbit basilar artery where (–)-nimodipine is more effective than (+)-nimodipine in relaxing the smooth muscle contracted by K⁺-depolarisation. It is concluded that cAMP phosphodiesterase may be an intracellular target for nimodipine and its inhibition may contribute to the pharmacological activity of this 1,4-dihydropyridine. Send offprint requests to Ch. Schachtele at the above address     

Stereoselective determination of R(−)- and S(+)-prilocaine in human serum using a brush-type chiral stationary phase,solid-phase extraction and UV detection

A chiral HPLC method was developed for the quantitation of R(−)- and S(+)-prilocaine in human serum. The method involves sensitive and selective detection of R(−)- and S(+)-prilocaine using normal-phase chiral HPLC on a pirkle-type naphthyl ethylamine stationary phase (Sumichiral OA-4700, 250 mm × 4 mm i.d.) at ambient temperature with a flow rate of 0.8 ml min⁻¹. A sample clean-up procedure was used for isolation of the analytes of interest from human serum using Bond-Elut C₁₈ columns with high recovery and selectivity. The detection limits were 4 ng ml⁻ for R-prilocaine and 5 ng ml⁻¹ for S-prilocaine. The limits of quantitation were 10 ng ml⁻¹ for both enantiomers. Linear calibration curves in the 10–1000 ng ml⁻¹ range showed good coefficients of determination >0.999 (n − 3). Precision and accuracy of the method were within 4–5.8% and 1.5–4.8% respectively for R(−)-prilocaine, and 2.8–5.7%, and 3.2–5.2% respectively for S(+)-prilocaine.     

Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes

Pharmaceutical Research - To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the...     

Effects of β2-agonist- and dexamethasone-treatment on relaxation and regulation of β-adrenoceptors in human bronchi and lung tissue

1. Long-term treatment with β₂-adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to β-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with β₂-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied.
2. The effect of β₂-agonist incubation alone and after coincubation with dexamethasone on density and affinity of β-adrenoceptors was investigated by radioligand binding experiments.
3. In human isolated bronchi, isoprenaline induces a time- and concentration-dependent β-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73±4% in efficacy of isoprenaline to relax human bronchial smooth muscle.
4. After an incubation period of 60 min with 100 μmol l⁻¹ terbutaline, a significant decline in its relaxing efficacy (81±8%) and potency (by a factor 5.5) occurred.
5. Incubation with 30 μmol l⁻¹ isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4).
6. Coincubation of dexamethasone with isoprenaline (120 min; 30 μmol l⁻¹) preserved the effect of isoprenaline on relaxation (129±15%).
7. In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 μmol l⁻¹) resulted in a decrease in β-adrenoceptor binding sites (B_max) to 64±1.6% (P<0.05), while the antagonist affinity (K_D) for [³H]-CGP-12177 remained unchanged.
8. In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 μmol l⁻¹) or isoprenaline (30 μmol l⁻¹) plus dexamethasone (30 μmol l⁻¹) for 120 min did not lead to a significant change of B_max (160±22.1% vs 142.3±28.7%) or K_D (5.0 nmol l⁻¹ vs 3.5 nmol l⁻¹) compared to the controls.
9. In conclusion, pretreatment of human bronchi with β-adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down-regulation of β-adrenoceptors. This effect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identification of mechanisms of β-adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable effects of long-term β-adrenoceptor stimulation.

     

Effects of Kollicoat IR® and hydroxypropyl-β-cyclodextrin on the dissolution rate of omeprazole from its microparticles and enteric-coated capsules

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR^® and hydroxypropyl-β-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P?<?0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40?min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR^® or hydroxylpropyl-β-cyclodextrin is considered a promising way to improvement of drug dissolution.     

The Metabolism of Amphetamine in vitro by Rabbit Liver Preparations: A Comparison of R(−) and S(+) Enantiomers

1. Incubation of R(?), S(+) and RS(±) amphetamines with rabbit liver 9000 g supernatant indicated that R(?) was metabolized at a faster rate than S(+), but that racemic amphetamine was metabolized at the same rate as S(+) during one hour incubations.

2. N-Hydroxyamphetamine and 1-phenyl-2-propanol were the major compounds detected in both R(?) and S(+) amphetamine incubations.

3. Phenylacetone oxime was detected in significant quantities after 3?h incubations of R(?) amphetamine, but only in minor quantities from S(+).

4. A fall in the amount of N-hydroxyamphetamine present in R(?) amphetamine incubations after a 3?h period as compared to a 1?h incubation, paralleled by a rise in the amount of phenylacetone oxime during 3?h suggested that the oxime was derived as a secondary metabolite from N-hydroxyamphetamine.

5. R(?) and S(+) N-hydroxyamphetamines were both metabolized to phenylacetone oxime by rabbit liver 9000 g supernatant, but the R(?) enantiomer was converted at a faster rate than S(+).     

Effects of the putative P-type calcium channel blocker,R,R-(−)-daurisoline on neurotransmitter release

The alkaloid and medicinal herb constituent, R,R-(–)-daurisoline, was originally reported to be a N-type Ca²⁺ channel blocker, but newer evidence indicates that it is a blocker of P-type Ca²⁺ channels. To clarify its specificity with respect to N- and P-channels, we compared its effects on the electrically induced release of endogenous glutamate, ³H-GABA and ³H-noradrenaline, from brain slices with those of -agatoxin IVA and -conotoxin GVIA. Like -agatoxin IVA (but with about 1000-fold lower potency), and unlike -conotoxin GVIA, R,R-(–)-daurisoline inhibited the release of ³H-GABA and glutamate, with IC₅₀ values of 8 and 18 M. However, inhibition particularly of ³H-GABA release was more complete than by -agatoxin IVA, indicating interaction with one or more additional voltage-sensitive Ca²⁺ channels, possibly the Q-type. Its potency to inhibit glutamate release elicited either electrically, by veratrine or by high concentrations of K⁺ was similar, in contrast to sodium channel blockkes. The effects of R,R-(–)-daurisoline on the release of ³H-noradrenaline, ³H-dopamine and ³H-acetylcholine were in agreement with previous knowledge from experiments with -agatoxin IVA suggesting an involvement of P-channels. A weak inhibition of ³H-noradrenaline release at 10 M, similar to that by -agatoxin IVA at 0.03 M, was occluded by ₂-antagonistic properties and could be unmasked in presence of rauwolscine. At 10 M, it also inhibited electrically evoked ³H-dopamine and ³H-5-hydroxytryptamine release and caused a marked spontaneous release of all three monoamines in a reserpine-like manner. Spontaneous and evoked release of ³H-acetylcholine was inhibited by about 25% at 10 M.In radioligand binding studies, R,R-(–)-daurisoline interacted with ₁ and ₂-adrenoceptors, 5-HT₂ and muscarinic cholinergic receptors with IC₅₀ values close to 1 M, and with opiate receptors even with 0.18 M. Atropine reduced the weak inhibitory effect of R,R-(–)-daurisoline on ³H-acetylcholine release somewhat, suggesting that it was brought about by both P channel blockade and cholinergic agonist activity. The effect on ³H-GABA release was unaffected by naloxone, indicating that the interaction of R,R-(–)-daurisoline with opiate receptors is antagonistic.The pattern of effects on neurotransmitter release observed with R,R-(–)-daurisoline resembles that of -agatoxin IVA and supports previous electrophysiological data suggesting that the compound blocks P-type voltage-sensitive Ca²⁺ channels. However, the more complete blockade of amino acid release by R,R-(–)-daurisoline suggests interaction with additional Ca⁺ channel subtypes. Although it does also possess other pharmacological properties, we think that the compound is suitable to test whether blockade of glutamate release via voltage-sensitive Ca²⁺ channels is a viable concept to obtain novel neuroprotective and/or anticonvulsant compounds.     

Effects of (−)-Phenylephrine on force of contraction in the presence of cocaine and hydrocortisone in cat papillary muscle

Summary The positive inotropic effect of (–)-phenylephrine, in the presence of propranolol, was studied after inhibition of neuronal and extraneuronal uptake in isolated papillary muscles from reserpine-pretreated cats. An inhibition of extraneuronal uptake with hydrocortisone influenced the effect of (–)-phenylephrine neither when present alone nor in the presence of cocaine (additional inhibition of neuronal uptake). An inhibition of neuronal uptake with cocaine caused a small but significant increase in the potency of (–)-phenylephrine. We conclude that in cat ventricular cardiac muscle the extraneuronal compartment is apparently neither a site of loss nor a site of gain for (–)-phenylephrine with respect to force of contraction.     

Effects of β-ODAP and its biosynthetic precursor on the electrophysiological activity of cloned glutamate receptors

3-N-Oxalyl- -2,3-diaminopropanoic acid (β-ODAP) induces neurolathyrism, a motor neuron disease. To elucidate the pathogenic mechanism of this process, the action of β-ODAP on the excitatory amino acid (EAA) receptor-mediated currents was examined using cloned EAA receptors expressed in Xenopus oocytes. On the voltage-clamp recordings of an AMPA receptor (₁/₂ heterooligomer), β-ODAP was a strong agonist on this receptor, the potency being almost the same as -glutamate. On the other hand, β-ODAP had little effect on the glutamate-evoked currents through the expressed NMDA receptor (NR1_A/NR2A), but showed a weak inhibitory effect on the glycine-modulatory site. β-ODAP may cause the neurodegenerative disease, neurolathyrism, mainly through the excitotoxic interaction with AMPA receptors.     

Comparison of interactions of R(+)- and S(−)-isomers of β-adrenergic partial agonists,befunolol and carteolol,with high affinity site of β-adrenoceptors in the microsomal fractions from guinea-pig ciliary body,right atria and trachea

• 1.1. The stereoselectivities of β-adrenergic partial agonists for the high affinity binding site of β-adrenoceptors in the guinea-pig ciliary body, right atria and trachea were studied.
• 2.2. The inhibition curves by the S(−)-isomers of befunolol and carteolol were not significantly different from that by the R(+)-isomers in the guinea-pig ciliary body.
• 3.3. The inhibition curves by the S(−)-isomers of befunolol and carteolol were about 10 times as potent as the R(+)-isomers in the guinea-pig atria and trachea.
• 4.4. The pK_i values of the S(−)-isomers of befunolol and carteolol were significantly larger than those of R(+)-isomers in the guinea-pig atria and trachea but not larger than those of the R(+)-isomers in the guinea-pig ciliary body.
• 5.5. These results suggest that the high affinity binding site of β-adrenoceptors in ciliary body cannot discriminate stereoselectively between the R(+)- and S(−)-isomers, while in other tissues there is stereoselectivity between the two enantiomers.

     

Effects of amlodipine therapy on the concentrations of intralymphocytic free calcium and angiotensin II and left ventricular diastolic function in primary

AIM: To investigate the relationship between the cardiac function and the intracellular calcium and the effect of calcium channel antagonist therapy. METHODS: We determined the blood pressure (BP), iontralymphocytic free calcium concentration([Ca~(2 )]_i), serum angiotensin Ⅱ     

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Rationale  Racemic propranolol (PRO), a β-adrenoceptor antagonist, has been evaluated as a test agent but not as a discriminative stimulus. Its S(−) stereoisomer is thought to subserve the effects of (±)PRO. Materials and methods  Rats were trained to discriminate S(−)PRO (5 mg/kg) from saline in a two-lever food-reinforced operant conditioning task. Results  The S(−)PRO stimulus was shown to be centrally mediated, dose-related, time dependent, and stereoselective: S(−)PRO (ED₅₀ = 2.2 mg/kg) was twice as potent as (±)PRO and approximately four times as potent as R(+)PRO. The S(−)PRO stimulus generalized fully to the β-adrenoceptor agent pindolol, the α₁-adrenoceptor agonist methoxamine, cocaine, and the serotonergic agents TFMPP and RU 24969; partial generalization occurred to (−)ephedrine and nisoxetine but not to fenfluramine or 5-OMe DMT. The S(−)PRO stimulus was blocked completely (and competitively) when prazosin, an α₁-adrenoceptor antagonist, was given in combination with the training dose of S(−)PRO. Moreover, prazosin exerted antagonism of the S(−)PRO-like effect of (±)PRO or R(+)PRO but produced only partial antagonism of the S(−)PRO-like effect of cocaine. In a second study, rats were trained to discriminate 8 mg/kg of cocaine from saline. The cocaine stimulus generalized to S(−)PRO, (±)PRO, and R(+)PRO. Prazosin partially attenuated the stimulus effect of cocaine (8 mg/kg) but completely blocked the cocaine-like effects of (±), S(−), and R(+)PRO. Conclusions  PRO and cocaine exhibited cross-substitution, but their stimulus effects were antagonized differentially by prazosin. PRO (and its optical isomers) can exert a stimulus effect that is based, at least in part, on increased α₁-adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist. This study was supported, in part, by the National Institute on Drug Abuse (NIDA) grant DA-01642.     

Determination of S/R ratio of mephenytoin in human urine by chiral HPLC and ultraviolet detection and its comparison with gas chromatography

目的：建立人尿中Ｒ，Ｓ美芬妥英的液相色谱手性分离与检测方法，用于ＣＹＰ２Ｃ１９酶活性的快速测定．方法：受试者口服消旋美芬妥英后的０－８ｈ尿液标本用二氯甲烷提取后用手性色谱柱进行分离，流动相为乙腈和水（１４∶８６，体积比），其中含有０．１％的冰醋酸和０．２％的三乙胺，流速为０．９ｍＬ·ｍｉｎ－１，紫外检测波长为２０７ｎｍ．结果：在选定的色谱条件下Ｒ，Ｓ美芬妥英能很好地分离，尿中其他物质无干扰．用外标法定量，线性范围在５０－５０００μｇ·Ｌ－１，最小检出浓度为１２．５μｇ·Ｌ－１，保留时间在９ｍｉｎ内．液相色谱分析结果和气相色谱分析具有良好的一致性．结论：该法样本制备简便、分析时间短、线性范围宽、干扰少、灵敏和准确，可用于人体内美芬妥英代谢的研究和肝药酶ＣＹＰ２Ｃ１９酶活性的检测     

Effects of a desealant formulation, SR-51(®) and its individual components on the oxidative functions of mitochondria

The Royal Australian Air Force has reported that personnel involved in F-111 fuel tank maintenance were concerned that exposure to a range of chemicals during the period 1977-mid-1990s was the cause of health problems. Particular concern was directed at a desealant chemical mixture known as SR-51(?). The current study, using in vitro submitochondrial assays, was designed to investigate the relative toxicities of the four components of SR-51(?) (Aromatic 150 solvent (Aro150), dimethylacetamide (DMA), thiophenol (TP) and triethylphosphate (TEP)). Based on the EC(50) values, TP and Aro150 were the most toxic components and were markedly more toxic than TEP and DMA.     

Effects of vinegar–egg on growth inhibition,differentiation human leukemic U937 cells and its immunomodulatory activity

Vinegar and eggs have rich nutrients. In this study, the mixed form of both derived products, vinegar–egg solution and its products (vinegar–egg concentrate and vinegar–egg condensate) were chosen for an assessment of their biological activity. To further our understanding regarding the anticancer and immunomodulatory effects of vinegar–egg, we investigated its effects on the proliferation and differentiation of U937 cells. Vinegar–egg was treated using spray drying, freeze drying and vacuum concentration and used to stimulate human mononuclear cells. The conditioned media obtained from these cultures by filtration were used to treat U937 cells. Three conditioned media inhibited U937 cell growth by 22.1–67.25% more effectively than PHA-treated control (22.53%). CD11b and CD14 expression on the treated U937 cells were 29.1–45.4% and 31.6–47.2%, respectively. High levels of cytokines IL-1β, IFN-γ and TNF-α were detected in the three conditioned media. Vinegar–egg stimulates human mononuclear cells to secrete cytokines, which inhibit the growth of U937 cells and induce their differentiation.     

Effects of anthocyanins on the AhR–CYP1A1 signaling pathway in human hepatocytes and human cancer cell lines

Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food–drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)–cytochrome P450 CYP1A1 signaling pathway in human hepatocytes and human hepatic HepG2 and intestinal LS174T cancer cells. Pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) dose-dependently activated AhR, as revealed by gene reporter assay. PEL-2 and CYA-3 induced CYP1A1 mRNA but not protein in HepG2 and LS174T cells. Neither compounds induced CYP1A1 mRNA and protein in four different primary human hepatocytes cultures. The effects of PEL-2 and CYA-3 on AhR occurred by ligand-dependent and ligand-independent mechanisms, respectively, as demonstrated by ligand binding assay. In a direct enzyme inhibition assay, none of the antocyanins tested inhibited the CYP1A1 marker activity to less than 50% even at 100 μM concentration. PEL-2 and CYA-3 at 100 μM inhibited CYP1A1 to 79% and 65%, respectively. In conclusion, with exception of PEL-2 and CYA-3, there were no effects of 19 major anthocyanins and 3 food supplements containing anthocyanins on AhR–CYP1A1 signaling, implying zero potential of these compounds for food–drug interactions with respect to AhR–CYP1A1 pathway.     

Effects of nornicotine enantiomers on intravenous <Emphasis Type="Italic">S</Emphasis>(−)-nicotine self-administration and cardiovascular function in rats

Rationale Previous neurochemical evidence indicates that R(+)-nornicotine is more potent than S(−)-nornicotine in evoking dopamine release in rat nucleus accumbens slices. Objective The current study tested the hypothesis that R(+)-nornicotine is also more potent than S(−)-nornicotine in selectively decreasing intravenous S(−)-nicotine self-administration in rats. Results After acute pretreatment (1–10 mg/kg for each enantiomer), R(+)-nornicotine was more potent than S(−)-nornicotine in decreasing S(−)-nicotine self-administration; in contrast, within the same dose range, the nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(−)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-nornicotine, but not to the effects of S(−)-nornicotine, across repeated treatments. Conclusion Both R(+)- and S(−)-nornicotine may have potential utility as a novel tobacco use cessation agent.     

Synergistic effect of (+)-pinitol from Saraca asoca with β-lactam antibiotics and studies on the in silico possible mechanism

Saraca asoca bark has been used in the Ayurvedic system of medicine for female urino-genital disorders. We have recently reported the isolation and characterization of several compounds as markers to develop HPLC profiling of its methanol and aqueous methanol extracts. Now, a HPLC-PDA inactive compound, (+)-pinitol has been isolated and characterized from the bark of this medicinally important tree. Pinitol is a well known bioactive compound for a variety of biological activities, including hypoglycemic and anti-inflammatory activities. A process for the isolation of relatively good concentration of (+)-pinitol from S. asoca bark has been developed and its in vitro anti TNF-α and anti-inflammatory activities against carragenan-induced edema confirmed. While conducting experiments on the possible agonistic activity, it was found that (+)-pinitol showed up to eight fold reduction in the doses of β-lactam antibiotics. The mechanism of its agonistic activity was studied by docking experiments which showed that different conformations of (+)-pinitol and antibiotics were actually in the same binding site with no significant change in the binding energy. These docking simulations, thus predict the possible binding mode of studied compounds and probable reason behind the synergistic effect of (+)-pinitol along with β-lactam antibiotics.