Optically active derivatives of imidazolines. alpha-Adrenergic blocking properties.

The synthesis and alpha-adrenergic blocking activity of a series of optically active 2,4-disubstituted imidazolines are presented. The substituted analogues of naphazoline, tolazoline, and clonidine possess moderate alpha-adrenergic blocking activity with -log KB values in the range from 4.77 to 6.57. The differences between the alpha-adrenergic blocking activity of the stereoisomers of the 2,4-disubstituted imidazolines were small or insignificant in the rabbit aortic tissue preparations.

Stereochemical studies of adrenergic drugs. Optically active derivatives of imidazolines.

The synthesis of (R)-(+)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (2) and (S)-(-)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (3) is presented. The synthesis involves the preparation of (R)-(+)- and (S)-(-)-1,2-diaminopropane dihydrochloride and then allowing the appropriate diaminopropane to react with ethyl 1-naphthyliminoacetate hydrochloride in the presence of triethylamine. The parent compound, naphazoline, is a potent alpha-adrenoreceptor agonist (-log ED50 = 7.22), whereas the methylated derivatives, 2 and 3, were moderately potent antagonists (pA2 = 5.6 and 5.8, respectively) of the alpha-adrenoreceptor. Compounds 2 and 3 also produced blockade of the response to histamine on the rabbit aorta, but at concentrations approximately 20 times higher than necessary to produce equal blockade of the alpha-adrenoreceptor.

Congeners of the alpha conformer of dopamine derived from octahydrobenz[h]isoquinoline.

Two synthetic paths have been investigated for the preparation of cis and trans 8,9-dioxygenated octahydrobenz[h]isoquinoline ring systems. A sequence involving intramolecular Diels--Alder cyclization of a ring-opened intermediate product of a benzocyclobutene derivative was more satisfactory. The trans-fused isomers of the title compounds are frozen congeners of the alpha conformer of dopamine, isomeric with certain other tricyclic heterocycles which elicit a high degree of dopamine agonist activity. However, the present series of compounds exhibited a very low potency in an assay for dopamine-like actions. A possible reason for this inactivity has been suggested.

Synthesis and alpha-adrenergic activities of 2- and 4-substituted imidazoline and imidazole analogues.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Preparation and biological actions of some symmetrically N,N-disubstituted dopamines.

The title compounds have been synthesized and evaluated for emetic effects in the dog, actions on the cardioaccelerator nerve in the cat, pecking in pigeons, and for behavioral effects following both peripheral and direct intracerebral injection into the nucleus accumbens and caudate-putamen of the rat. Generally, in the series studied, the N,N-diethyl and N,N-di-n-propyl congeners of dopamine displayed notably high degrees of activity. However, the test compounds exerted differing effects on peripheral and central dopamine receptors and in the area postrema. Differentiations of the activities of the different homologues within the brain were also shown.

Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with alpha 2-adrenoceptors involving a "methyl pocket".

The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the alpha 2-adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent alpha 2-adrenoceptor binding ligand among these 4-substituted imidazoles, and its alpha 2-adrenoceptor selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize alpha 2-adrenoceptor binding data of the imidazole analogs in terms of ligand-receptor interactions. The structure-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the alpha 2-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the alpha-methyl group of (-)-alpha-methylnorepinephrine and fit into the proposed "methyl pocket" of the alpha 2-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.

Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

ADP-mimicking platelet aggregation caused by rugosin E, an ellagitannin isolated from Rosa rugosa Thunb.

Among the nine ellagitannins, rugosin E was the most potent platelet aggregating agent with an EC50 of 1.5 +/- 0.1 microM in rabbit platelets and 3.2 +/- 0.1 microM in human platelets. The aggregations caused by rugosin E and ADP were inhibited by EGTA, PGE1, mepacrine, sodium nitroprusside and neomycin, but not by indomethacin, verapamil, TMB-8, BN52021 and GR32191B. Rugosin E-induced thromboxane formation was suppressed by indomethacin, EGTA, PGE1, verapamil, mepacrine, TMB-8 and neomycin. ADP-scavenging agents, such as CP/CPK and apyrase inhibited concentration-dependently ADP (20 microM)-, but not rugosin E (5 microM)-induced platelet aggregation. In thrombin (0.1 U/ml)-treated and degranulated platelets, rugosin E and ADP still caused 63.5 +/- 3.0% and 61.2 +/- 3.5% of platelet aggregation, respectively. Selective ADP receptor antagonists, ATP and FSBA inhibited rugosin E- and ADP-induced platelet aggregations in a concentration-dependent manner. Both rugosin E and ADP did not induce platelet aggregation in ADP (1 mM)-desensitized platelets. In contrast to ADP, rugosin E did not decrease cAMP formation in washed rabbit platelets. Both rugosin E and ADP did not cause phosphoinositide breakdown in [3H]myo-inositol-labeled rabbit platelets. In fura-2/AM-load platelets, both rugosin E and ADP induced increase in intracellular calcium concentration and these responses were inhibited by ATP and PGE1. All these data suggest that rugosin E may be an ADP receptor agonist in rabbit platelets.

Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats.

Wistar rats with streptozotocin-induced diabetes (STZ-diabetic rats), which is similar to human insulin-dependent diabetic mellitus (IDDM), were employed to investigate the antihyperglycemic action of isoferulic acid. A single intravenous injection of isoferulic acid decreased the plasma glucose in a dose-dependent manner in the STZ-diabetic rats. Repeated intravenous administration of STZ-diabetic rats with isoferulic acid (5.0 mg kg(-1)) also resulted in the lowering of plasma glucose after one day. Stimulatory effects of isoferulic acid on the glucose uptake and glycogen synthesis in soleus muscles isolated from STZ-diabetic rats were also obtained indicating an increase of glucose utilization following isoferulic acid treatment which was not dependent on insulin. The mRNA level of glucose transporter subtype 4 form (GLUT4) in soleus muscle was raised by isoferulic acid after repeated treatment for 1 day in STZ-diabetic rats. Similar repeated treatment with isoferulic acid reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level. However, expression of GLUT4 and PEPCK genes in nondiabetic rats were not influenced by similar treatment with isoferulic acid. These results suggest that isoferulic acid can inhibit hepatic gluconeogenesis and/or increase the glucose utilization in peripheral tissue to lower plasma glucose in diabetic rats lacking insulin.

Differential inhibition of reverse transcriptase and cellular DNA polymerase-alpha activities by lignans isolated from Chinese herbs, Phyllanthus myrtifolius Moon, and tannins from Lonicera japonica Thunb and Castanopsis hystrix.

Two lignans, phyllamycin B and retrojusticidin B isolated from Phyllanthus myrtifolius Moon have been demonstrated to have a strong inhibitory effect on human immunodeficiency virus-1 reverse transcriptase activity (HIV-1 RT), but much less inhibitory effect on human DNA polymerase-alpha (HDNAP-alpha) activity. Fifty percent inhibitory concentrations of phyllamycin B and retrojusticidin B were determined to be 3.5 and 5.5 microM for HIV-1 RT, and 289 and 989 microM for HDNAP-alpha, respectively. The mode of inhibition was found to be non-competitive inhibition with respect to template-primer and triphosphate substrate. Several tannins such as caffeoylquinates (CQs) isolated from Lonicera japonica Thunb, galloylquinates (GQs) and galloylshikimates (GSs) purified from Castanopsis hystrix were shown to have a much less selective inhibitory effect on HIV-1 RT.

Inhibitory Effects of Polyphenolic Catechins from Chinese Green Tea on HIV Reverse Transcriptase Activity.

Three polyphenolic catechins, epigallocatechin (1), epicatechin-3-O-gallate (2) and epigallocatechin-3-O-gallate (3), were isolated from Chinese green tea, Ti-Kaun-Yin (Camellia sinensis) and demonstrated as a new class of human immunodeficiency virus-reverse transcriptase (HIV-RT) inhibitor. The concentrations required for 50% inhibition for the compounds (1), (2) and (3) were 7.80, 0.32 and 0.68 &mgr;M, respectively. The polyphenolic catechins with a galloyl group at the 3 position were potent inhibitors of HIV-RT. Kinetic analysis indicated that the polyphenolic catechins were competitive inhibitors with respect to the template-primer (rA)(n)(dT)(12-18) and noncompetitive inhibitors to dTTP. Copyright 1994 S. Karger AG, Basel

Inhibition of platelet activation and endothelial cell injury by flavan-3-ol and saikosaponin compounds.

The effects of flavan-3-ol and saikosaponin compounds on platelet aggregation, platelet thromboxane biosynthesis and H2O2-induced endothelial cell injury were studied. Seven flavan-3-ol compounds isolated from Camellia sinensis L. var sinensis O. Kuntze (Theaceae) and three saikosaponin compounds isolated from Bupleurum falcatum L. (Umbelliferae) were used. Among the 10 compounds tested, only epigallocatechin and saikosaponin a significantly inhibited human platelet aggregation induced by ADP, and the potency of inhibition was comparable with aspirin. Both of epigallocatechin and saikosaponin a dose-dependently inhibited the platelet thromboxane formation from exogenous and endogenous arachidonic acid. In the prevention of H2O2-induced endothelial cell injury in culture, only gallocatechin-3-0-gallate and epicatechin-3-0-gallate were effective. The inhibitory effect of epigallocatechin and saikosaponin a on platelet activation and the cytoprotective effect of gallocatechin-3-0-gallate and epicatechin-3-0-gallate on H2O2-induced endothelial cell injury could give evidence of explaining the possible role of flavan-3-ol and saikosaponin compounds in maintaining vascular homeostasis.

Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins.

The effects of procyanidins on platelet aggregation and arachidonate metabolism in platelets were studied. Nine procyanidins were used in this investigation. Procyanidins B-2-S, EEC and C-1 significantly induced the inhibition of platelet aggregation, and the potency of inhibition was comparable with aspirin. Procyanidin B-2-S was used as a representative of procyanidins for further studies on the effect on arachidonate metabolism. In arachidonate metabolism by fatty acid cyclooxygenase pathway, B-2-S inhibited TXB2 and HHT formation by intact platelets treated with exogenous arachidonic acid. It also inhibited TXB2 formation measured by a specific radioimmunoassay when the cells were challenged with calcium ionophore A23187. In cell-free system, B-2-S inhibited both TXB2 and 12-HETE bioxynthesis in platelet microsome and cytosol, respectively. The inhibitory effect on thromboxane biosynthesis might explain the inhibitory effect of procyanidins on platelet aggregation.

Inhibition of platelet activation and endothelial cell injury by polyphenolic compounds isolated from Lonicera japonica Thunb.

Effects of the polyphenolic compounds isolated from Lonicera japonica Thunb on platelet aggregation, platelet thromboxane biosynthesis and hydrogen peroxide-induced endothelial cell injury were studied. With regard to the inhibitory effect on human platelet aggregation, methyl caffeate, 3,4-di-O-caffeoylquinic acid and methyl 3,4-di-O-caffeoylquinate had a strong effect. They significantly inhibited the second wave of platelet aggregation induced by ADP. Concerning thromboxane biosynthesis triggered by calcium ionophore A23187 in platelets, methyl caffeate and methyl 3,4-di-O-caffeoylquinate had the most potent inhibitory effect. Methyl 3,4-di-O-caffeoylquinate directly inhibited the conversion of arachidonic acid to thromboxane by platelet microsomes, while methyl caffeate did not have any significant effect on thromboxane biosynthesis in platelet microsomes. In the prevention of hydrogen peroxide-induced endothelial cell injury in culture, protocatechuic acid, methyl caffeate, methyl chlorogenic acid and luteolin were significantly effective. The inhibitory effect on platelet activation and the cytoprotective effect on hydrogen peroxide-induced cell injury may explain the possible role of polyphenolic compounds isolated from Lonicera japonica Thunb in maintaining vascular homeostasis.

Inhibition of synaptosomal uptake of norepinephrine and dopamine by conformationally restricted sympathomimetic amines.

The conformationally restricted cis and trans isomer of substituted cyclobutanes were examined for their ability to inhibit 3H-norepinephrine and 3H-dopamine accumulation by synaptosomes prepared from the cortex and corpus striatum, respectively. The drugs were more effective in preventing the accumulation of 3H-norepinephrine by cortical synaptosomes than 3H-dopamine by striatal synaptosomes. However, in the synaptosomes isolated from both regions, the trans isomers were more potent inhibitors of accumulation than the cis isomers. The greatest stereoselectivity was exhibited by the isomers of 2-amino-1-phenylcyclobutanol. The accumulation of 3H-norepinephrine by cortical synaptosomes and the accumulation of 3H-dopamine by striatal synaptosomes were inhibited 50% by concentrations of the trans isomer of 7.4 X 10(-6) M and 1.7 X 10(-4) M, respectively. The cis isomer was inactive. In separate experiments, the releasing capabilities of the restricted analogs were determined by superfusing cortical and striatal synaptosomes labelled in vitro with 3H-catecholamines. The trans and cis isomers elicited a trivial release of 3H-norepinephrine and 3H-dopamine from cortical and striatal synaptosomes, respectively. The results indicate that the decreased synaptosomal accumulation of 3H-catecholamines caused by the analogs was due mainly to inhibition of uptake. The influence of dihydral angle between phenyl--NH2 on the inhibition of uptake is discussed. It is concluded that the anti conformation of sympathomimetic amines is the preferred conformation at the noradrenergic amine pump.

Stimulatory effect of paeoniflorin on adenosine A-1 receptors to increase the translocation of protein kinase C (PKC) and glucose transporter (GLUT 4) in isolated rat white adipocytes.

In an attempt to understand the subcellular signals after activation of adenosine A-1 receptors, paeoniflorin was employed to incubate with rat white adipocytes in vitro. Translocation of protein kinase C (PKC) beta-subtype from cytosol to membrane was enhanced by an incubation with paeoniflorin in a concentration-dependent manner similar to that of porcine insulin. Also, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) inhibited this action of paeoniflorin in a concentration-related fashion and it markedly attenuated the action of paeoniflorin at a concentrations sufficient to block the action of adenosine. Moreover, chelerythrine inhibited the paeoniflorin-stimulated translocation of PKC in a way similar to that stimulated by porcine insulin. Subcellular inhibition is considered because stimulation of porcine insulin was not modified by DPCPX at concentrations sufficient to block adenosine A-1 receptors. Similar results were also observed in adipocytes regarding the translocation of glucose transporter (GLUT4) from cytosol to membrane. Thus, we found that paeoniflorin can activate adenosine A-1 receptors to increase the translocations of PKC and GLUT4, two major signals for glucose uptake, from cytosol to membrane of the white adipocytes in rats.

The effects of cantharidin analogues on xanthine oxidase.

Norcantharidin[3], the demethylated product of cantharidin[1] has been used for the treatment of hepatoma, carcinomas of esophagus and gastric cardia, leukopenia and hepatitis. Since the enzyme xanthine oxidase is involved in the diseases mentioned above, and the reactive oxygen species produced by the enzyme induces DNA damage and oxidative damage of tissues, fourteen cantharidin analogues and cantharidimide derivatives were tested for their effects on xanthine oxidase. The results showed that these compounds, listed in Figure 1, displayed very weak inhibitory effects on xanthine oxidase. Contrary to expectation, disodium cantharidate [2], Norcantharidin [3], dehydronorcantharidin [4], disodium dehydronorcantharidate [5], N-(2-pyridyl) cantharidimide [12], N-(3pyridyl) cantharidimide [13] and N-(4-pyridyl) cantharidimide [14] showed a slight stimulating effect on xanthine oxidase at several concentrations.

O-demethylation of pyrilamine.

O-Demethylation of pyrilamine with l-propanethiol and potassium tert-butoxide gave hydroxytripelennamine, one of the major metabolites of tripelennamine. The reaction of pyrilamine with other demethylating agents has been explored and the products formed have been characterized. The reaction of pyrilamine with 48% hydrobromic acid yielded 2-(2-dimethylaminoethyl)aminopyridine. When a mild, neutral demethylating agent, Me3Sil, was used, 2,3-dihydroimidazopyridinium iodide was the sole product formed.

Synthesis and anticholinesterase activity of new bispyridinium compounds.

Synthesis of new bis(1-methylpyridinium) compounds containing a 1,4-diacetylbenzene linkage between the pyridinium moieties from commercially available 2-, 3-, and 4-picoline precursors was accomplished via metallation, reaction of the picolyllithium with 1,4-dicyanobenzene, and subsequent quaternization of the resulting bispyridyl compounds. Acetylcholinesterase inhibitory activity was determined colorimetrically with purified electric eel enzyme. Examination of structure-activity relationships indicated that the 3-substituted pyridinium compound is the most potent isomer, followed by the 2-substituted isomer, and that the 4-substituted analogue is the least active.