1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part II]

Indole-3-carbinol (I3C) (2) is produced endogenously from naturally occurring glucosinolates contained in a wide variety of plant food substances including members of the family Cruciferae, and particularly members of the genus Brassica, whenever they are crushed or cooked. The acid environment of the gut very facilely converts it into a range of polyaromatic indolic compounds, e.g. (3, 4,5), which appear to be responsible for many of the physiological effects observed following the ingestion of these foods. These so-called chemopreventive compounds are important because of their enzyme induction and suppression, mutagenic, carcinogenic and, particularly, antimutagenic and anticarcinogenic properties against a variety of classes of carcinogens. These properties as well as other miscellaneous properties of these substances are critically reviewed in detail in this paper of >170 references, the second of two parts. At the present time it appears that I3C and its congeners have considerable potential as natural prophylactic anticancer agents against certain common neoplasms, especially inasmuch modern diets are increasingly deficient in these vegetable-derived substances. A short general assessment of the substantial potential of the title compounds concludes the review.     

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602)

A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.     

Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (I) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.8, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SERT site.     

Preparation of 8-[3-(4-fluorobenzoyl)-propyl]-1-(4-[123I] iodobenzoyl)-1,3,8-triazaspiro[4,5]decan-4-one: a novel selective serotonin 5-HT2 receptor agent

OBJECTIVE: to evaluate the effectiveness of a reduced-frequency prenatal visit schedule by comparing perinatal outcomes, anxiety and maternal satisfaction with prenatal care. METHODS: pregnancy outcomes of infant and maternal morbidity and mortality, anxiety and satisfaction for 81 women receiving prenatal care at a free-standing birthing center according to either an alternative prenatal care visit schedule (APCVS) (n = 43) or the traditional prenatal care visit schedule (TPCVS) (n = 38) were examined in this prospective randomized study. Upon entry into prenatal care, all women were of low obstetrical risk status. RESULTS: major findings revealed no significant differences in selected perinatal outcomes between the two study groups. Women in the APCVS group reported significantly higher levels of satisfaction than women in the TPCVS group on both the satisfaction with provider subscale (F = 5.74, P = .02) and the satisfaction with the prenatal care system subscale (F = 2.01, P = .04). There were no statistically significant differences found in anxiety scores between women in the two study groups. CONCLUSIONS: low-risk women who followed the reduced-frequency visit schedule experienced no difference in perinatal outcomes or anxiety. Women in the reduced-frequency (APCVS) group reported an increased level of satisfaction with both provider and the prenatal care system.     

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.     

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2A and h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPgammaS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1A autoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).     

Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of the piperazine ring of 1-[2-(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)

The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the sigma receptors (e.g.28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.     

Preparation of 5-[131I]iodo- and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil by a halodestannylation reaction

Because acquired immunodeficiency syndrome (AIDS) is a shifting endpoint and sufficient follow-up data now allow modeling of survival time (i.e., time from human immunodeficiency virus (HIV) seroconversion to death), the authors evaluated non-parametric and parametric models of mortality with the use of data from 554 seropositive participants in the Vancouver Lymphadenopathy-AIDS Study. The authors then applied these models to quantify treatment benefits at the national level in Canada, using back-calculation and forward-projection based on death registries. The study revealed that the lognormal model better describes survival time than the Weibull model. Relative to observations prior to 1987, later observations (in the era of treatment) revealed a statistically significant change in disease progression: the median survival time increased from 10.1 to 12.0 years, but no further survival improvements were observed in the early 1990s. Concurrent with the increase in availability of treatment, the authors have observed pronounced treatment benefits at the national level: prior to 1995, approximately 1,500 deaths were prevented and 4,200 person-years of life were saved. Also, mortality rates were observed to level off in the mid-1990s due to the shape of the historical HIV infection curve and the accumulating availability of treatment in Canada.     

Studies on anti-inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5- [4-(methylsulfinyl)phenyl]pyrazole and related compounds

A series of novel 1,5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30 = 0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50 = 21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.     

SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H- imidazole hydrochloride) stimulates phosphoinositide hydrolysis in human U373 MG astrocytoma cells

SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imi dazole hydrochloride) stimulated the accumulation of [3H]inositol monophosphates ([3H]IP1) in human U373 MG astrocytoma cells prelabelled with [3H]inositol (EC50 15 +/- 1 microM, Hill coefficient 3.8 +/- 0.4). SK&F 96365-induced accumulation of [3H]IP1 increased linearly with time, but there was no initial rapid formation of [3H]IP3. SK&F 96365 also stimulated [3H]IP1 accumulation in human HeLa cells, but only to a small extent in slices of rat cerebral cortex and guinea-pig cerebellum. SK&F 96365-induced accumulation of [3H]IP1 in U373 MG cells increased as extracellular Ca2+ was increased from nominally zero to 4 mM, but there was no evidence that SK&F 96365 induced any marked entry of Ca2+ into cells; only an inhibition of store-refilling-induced Ca2+ entry was apparent. Further, the response to SK&F 96365 was additive with that to the Ca2+ ionophore ionomycin. Depolarization of the cells with raised K+ produced only a small stimulation of phosphoinositide hydrolysis. SK&F 96365 caused the release of Ca2+ from intracellular stores in U373 MG cells (EC50 26 +/- 14 microM), but thapsigargin induced only a small accumulation of [3H]IP1. Miconazole, another N-substituted imidazole, also stimulated [3H]IP1 accumulation in U373 cells.     

YM022 [(R)-1-[2,3-dihydro-1-(2''-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea]: an irreversible cholecystokinin type-B receptor antagonist

It is controversial whether osteopontin (OP) is expressed in glomeruli and involved in glomerular diseases. We examined whether the OP expression is present at gene and protein levels in cultured rat mesangial cells (MCs). Northern blotting revealed a 1.7 kb OP-mRNA expression in MCs. Fetal calf serum (FCS) and TNF-alpha increased OP gene expression in serum-starved MCs by 2.7- and 1.8-fold over 24- and 12-hour periods, respectively. PDGF, IL-1beta, and TGF-beta had little effect on OP gene expression. Western blotting detected the OP protein expression (69 kDa). FCS and TNF-alpha increased OP protein expression in serum-starved MCs over 48- and 24-hour periods, respectively. The present study clearly demonstrated the expression of OP gene and protein in cultured rat MCs. Increased OP production under serum or TNF-alpha stimulation suggests that intraglomerular OP may contribute to the development of glomerular diseases.     

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: II. Functional profile in comparison to clozapine and haloperidol

S 16924 antagonized locomotion provoked by dizocilpine and cocaine, reduced conditioned avoidance responses and blocked climbing elicited by apomorphine, models predictive of control of the positive symptoms of schizophrenia: its median inhibitory dose (ID)50 was 0.96 mg/kg, s.c. vs. 1.91 for clozapine and 0.05 for haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D1 agonist, SKF 38393, and by the D2 agonist, quinpirole, was blocked equipotently by S 16924 (0.8 and 1. 7) and clozapine (0.6 and 2.0), whereas haloperidol preferentially blocked quinpirole (0.02) vs. SKF 38393 (1.8). S 16924 more potently inhibited the head-twitches elicited by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by phencyclidine than it inhibited the locomotion elicited by amphetamine (ID50s = 0.15 and 0.02 vs. 2.4). Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not haloperidol (0. 07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by S 16924 (ID50 = 0.17) and clozapine (0. 05) but not by haloperidol (>0.16). S 16924 fully (100%) generalized [effective dose (ED)50 = 0.7] to a clozapine DS and clozapine (0.23) fully generalized to a S 16924 DS whereas haloperidol (>/=0.08) only partially generalized (/=80.0) or clozapine (>/=80.0). Further, S 16924 (ID50 = 3.2) and clozapine (5.5) inhibited induction of catalepsy by haloperidol. This action of S 16924 was abolished by the 5-HT1A receptor antagonist, WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of clozapine. Further, although gnawing elicited by methylphenidate was inhibited by S 16924 (ID50 = 8.4), clozapine (19.6) and haloperidol (0.04), only the action of S 16924 was blocked by WAY 100,635 (0.16). Haloperidol potently (0.01-0.16, approximately 24-fold) increased prolactin levels whereas they were less markedly affected by S 16924 (2.5-40.0, 4-fold) and clozapine (10.0-40.0, 3-fold). Clozapine displayed high affinity at cloned, human, muscarinic (M1) and native, histamine (H1) receptors (Kis = 4.6 and 5.4 nM, respectively), whereas S 16924 (>1000 and 158) and haloperidol (>1000 and 453) displayed low affinity. In conclusion, S 16924 displays a profile of activity in diverse models of potential antipsychotic and extrapyramidal properties similar to that of clozapine and different to that of haloperidol. In particular, reflecting its partial agonist actions at 5-HT1A receptors, S 16924 inhibits rather than induces catalepsy in rats. However, in contrast to clozapine, S 16924 displays only low affinity for muscarinic and histaminic receptors.     

Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors

A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.     

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.     

Synthesis and biological activities of optically active 6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolinone (OPC-18790)

The enantiomers of 6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolinon e (OPC-18790), a novel cardiotonic agent, were synthesized and evaluated for positive inotropic activity. The key intermediates, 2,3-epoxypropoxy derivatives, were obtained by the alkylation of 6-hydroxy-2(1H)-quinolinone with optically active epichlorohydrin and subsequent ring closure. In an in vitro study, the (R)-(+)-isomer was about 10-fold more potent than the (S)-(-)-isomer.     

Molecular modeling of (E)-1-alkyl-4(3)-[2-(1H-azolyl)vinyl]-pyridinium salts and evaluation of their behavior towards choline acetyltransferase

A new type of extended pi-system aza-analogue of (E)-4-[2-(1-naphthylvinyl)]-1-substituted pyridinium salts (NVP+) has been designed and its inhibitory activity towards choline acetyltransferase (ChAT) has been evaluated in vitro. Among the several examples of the title quaternary salts synthesized 2 and 3, the indolylvinylpyridinium salt 2e is the only one to show a very low ChAT inhibition. The molecular modeling study is highly illustrative of their behavior towards ChAT and interaction with the recognition site. Thus, several selected cations together with the reference NVP+ compound 1a were studied at the PM3 and AM1 levels respectively. At the global minima, all the compounds are planar, which, from the electron charge distribution, shows a degree of polarization similar to the NVP+ model compound 1a. However, the fitting of all optimized structures indicated that only the indole derivative 2e showed the same aromatic fragment orientation as 1a, which allows us to define a volume that is not accessible to ligands in the enzyme and consequently to a refined model of the choline acetyltransferase recognition site.     

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties

Lactate dehydrogenase from the malarial parasite Plasmodium falciparum has many amino acid residues that are unique compared to any other known lactate dehydrogenase. This includes residues that define the substrate and cofactor binding sites. Nevertheless, parasite lactate dehydrogenase exhibits high specificity for pyruvic acid, even more restricted than the specificity of human lactate dehydrogenases M4 and H4. Parasite lactate dehydrogenase exhibits high catalytic efficiency in the reduction of pyruvate, kcat/Km = 9.0 x 10(8) min(-1) M(-1). Parasite lactate dehydrogenase also exhibits similar cofactor specificity to the human isoforms in the oxidation of L-lactate with NAD+ and with a series of NAD+ analogs, suggesting a similar cofactor binding environment in spite of the numerous amino acid differences. Parasite lactate dehydrogenase exhibits an enhanced kcat with the analog 3-acetylpyridine adenine dinucleotide (APAD+) whereas the human isoforms exhibit a lower kcat. This differential response to APAD+ provides the kinetic basis for the enzyme-based detection of malarial parasites. A series of inhibitors structurally related to the natural product gossypol were shown to be competitive inhibitors of the binding of NADH. Slight changes in structure produced marked changes in selectivity of inhibition of lactate dehydrogenase. 7-p-Trifluoromethylbenzyl-8-deoxyhemigossylic acid inhibited parasite lactate dehydrogenase, Ki = 0.2 microM, which was 65- and 400-fold tighter binding compared to the M4 and H4 isoforms of human lactate dehydrogenase. The results suggest that the cofactor site of parasite lactate dehydrogenase may be a potential target for structure-based drug design.     

Synthesis, gastroprotective, antisecretory and anti-Helicobacter effect of N-[3-(3-(1-piperidinylmethyl) phenoxy)propyl]-hydroxyacetamide 2-hydroxypropane-1,2,3-tricarboxylate bismuth (3+) complex (MX1)-MX1

Dental stone molds are convenient for fabricating facial prostheses, but they tend to break when repeatedly used to make duplicate prostheses. This study investigated the use of an inexpensive plastic mesh, die hardener, and PVC pipe segment to reinforce stone mold test samples that were broken in compression on an Instron testing machine. The samples reinforced with PVC pipe surpassed the load limit of the Instron machine. The samples reinforced with both die hardener and mesh were 13% more resistant to breakage than the control samples made of stone alone. Samples reinforced only with mesh were 3% weaker than the control samples.     

Synthesis and beta-adrenoreceptor blocking activity of [[3-(alkylamine)-2-hydroxypropyl]oximino]pyridines and O[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes derivatives

[[3-(alkylamine)-2-hydroxypropyl]-2-oximino]pyridines and O-[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes 5a-o were synthesized by a solid-liquid phase-transfer reaction, and their beta-adrenoreceptor blocking activity was evaluated in vitro and in vivo. The replacement of the aryl linked to the oximic carbon of the (methylenaminoxy)methyl moiety with the bioisoster pyridine ring produced a decrease of the beta-adrenergic blocking activity. The polarization of the oximic group, derived from the electron-withdrawing action of the nitrogen atom, is more evident for the 2-oxyminopyridine derivative 5d. But also conformational parameters may play an important role in the variation of activity of the compounds 5d, 5l and 5n. The replacement of the hydrogen linked to the oximic carbon with a methyl group increased the activity of the compounds 5a, 5i, 5m and 5o. The methyl could allow a delocalization of the partial positive charge present on the oximic carbon, but also its lipophilicity contributed to the increment of binding to the receptor site. None of the compounds showed high beta 1 or beta 2 selectivity in vitro. The (R) and (S) isomers of the compound 5a were synthesized and obtained with enantiomeric ratio 7:3 and 6:4, respectively. The binding tests and the pharmacological in vivo results confirmed the in vitro data.