AIMTo get some novel potent compounds with NOS inhibitory activity, a series of new compounds of isothioureas derived from 1,2,3,4-tetrahydroisoquinoline were synthesized.

METHODS1,2, 3,4-Tetrahydroisoquinol-2-yl was introduced into the structure of isothioureas, the NOS inhibitory activity of the new compounds synthesized were measured.

RESULTS AND CONCLUSIONTwenty-two isothiourea derivatives of [alkyl(or aryl) imino] (1,2,3,4-tetrahydroisoquinol-2-yl) methyl alkyl thioethers (I) and S-alkyl-1-phenyl-3-[4-(1,2,3,4-tetrahydroisoquinol-2-yl) methane] phenyl isothioureas (II) were synthesized from thioureas by S-alkylation with alkyl halides, and their structures were identified by IR, 1H NMR, MS and elemental analysis. The preliminary biological test showed that the part of type I (1-9 and 1-13) had higher NOS inhibitory activity than that the control aminoguanidine (AG), but the type II had weak ability to inhibit NOS.

Molecular Structure ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Stereoisomerism ; Tetrahydroisoquinolines ; chemistry ; Thiourea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

Animals ; Disease Models, Animal ; Liver ; parasitology ; Mice ; Mice, Inbred BALB C ; Schistosomiasis japonica ; immunology ; Thiourea ; analogs & derivatives ; pharmacology

AIMTo synthesize a series of 2-arylimino-4-thiazolidone derivatives and 2-imidazolino [2,3-b]-4-thiazolidone in order to get some novel potent compounds with nitric oxide synthases (NOS) inhibitory activity.

METHODSThe target compounds were prepared by reaction of N-chloroacetyl-1,2,3,4-tetrahydroisoquinoline or N-chloroacetylphthalimide with substituted thioureas, their NOS inhibitory activity were measured.

RESULTS AND CONCLUSIONThe 15 new compounds were synthesized and most of the reaction yields were over 65%. The structures of new compounds were identified by IR, 1H NMR, MS and elemental analyses. Bioassay indicated that, most of 15 new compounds synthesized had confirmed bioactivities inhibition against NOS.

Molecular Structure ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Structure-Activity Relationship ; Thiazoles ; chemical synthesis ; chemistry ; pharmacology ; Thiourea ; analogs & derivatives

The present study was aimed to investigate the positive inotropic mechanism of carbachol (CCh) on rat ventricular myocytes. The effects of CCh on L-type calcium current (I(Ca,L)) and Na(+)/Ca(2+) exchange current (I(Na/Ca)) were investigated in isolated rat ventricular myocytes. After loading myocytes with Fura-2/AM, electrically triggered Ca(2+) transient and cell shortening in single myocyte were measured simultaneously using ion imaging system with charge-coupled device (CCD) camera. CCh (100 mumol/L) increased I(Na/Ca) in forward mode from (1.18 +/- 0.57) pA/pF in the control group to (1.65 +/- 0.52) pA/pF (P<0.01) and that in reverse mode from (1.11 +/- 0.49) pA/pF in the control group to (1.53 +/- 0.52) pA/pF (P<0.01), respectively. CCh had no effect on I(Ca,L). The stimulatory effect of CCh on I(Na/Ca) was blocked by application of atropine, a non-selective M muscarinic receptor antagonist, and methoctramine, a selective M(2) muscarinic receptor antagonist. CCh (100 mumol/L) increased cell shortening from (3.00 +/- 0.67) mum in the control group to (3.55 +/- 1.21) mum. Ca(2+) transient was also increased from 203.8 +/- 50.0 in the control group to 234.8 +/- 64.3 in 100 mumol/L CCh group. KB-R7943, a selective inhibitor of reverse mode Na(+)/Ca(2+) exchange, did not change the baseline level of cell shortening and Ca(2+) transient, while completely abolished CCh-induced increments of both Ca(2+) transient and cell shortening. CCh increased cell shortening and Ca(2+) transient in the presence of nicardipine, indicating that the positive inotropic effect of CCh was through activation of Na(+)/Ca(2+) exchange. Calcium sensitivity was not changed by CCh. Both atropine and methoctramine abolished the positive inotropic effects of CCh, demonstrating that CCh induced positive inotropism via the M(2) muscarinic receptor. The results suggest that CCh increases cell contraction and Ca(2+) transient in rat ventricular myocytes. This positive inotropic effect of CCh is through activation of reverse mode Na(+)/Ca(2+) exchange, and M(2) receptors are involved in mediating CCh-induced contraction.
Animals ; Calcium ; Carbachol ; pharmacology ; Heart Ventricles ; Male ; Myocardial Contraction ; Myocytes, Cardiac ; drug effects ; Rats ; Receptor, Muscarinic M2 ; Receptors, Muscarinic ; drug effects ; Sodium ; Sodium-Calcium Exchanger ; Thiourea ; analogs & derivatives

Basing on the market multi-target antitumor agent sorafenib, a series of sixteen 4-[4-(2-methyl-aminoacyl-pyridyl)]oxylphenyl aryl thiourea derivatives were designed and synthesized. Their structures were identified by the spectra of 1H NMR, MS and elemental analysis. The evaluation of antitumor bioactivities in vitro was done by MTT method. It was shown that the synthesized compounds had antitumor activities and compounds 1a, 1d, 1i and 1j showed better or equal antitumor activity on sorafenib.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Molecular Structure ; Niacinamide ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Phenylurea Compounds ; chemical synthesis ; chemistry ; pharmacology ; Thiourea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-kappaB (NF-kappaB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-kappaB subunits. Concomitantly, the expression of NF-kappaB target genes such as IL-1beta, IL-6, TNF-alpha and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.
Animals ; Anti-Inflammatory Agents/*therapeutic use ; Benzoxazines/*therapeutic use ; Liver/*drug effects/immunology/*injuries/pathology ; Male ; Mice, Inbred C57BL ; NF-kappa B/immunology ; Reperfusion Injury/*drug therapy/immunology/pathology ; Signal Transduction/drug effects ; Thiourea/*analogs & derivatives/therapeutic use

OBJECTIVETo investigate the mechanisms of histamine on chronic epilepsy induced by pentylenetetrazole (PTZ).

METHODSTo induce chemical kindling, a subconvulsive dose (35mg/kg) of PTZ was ip injected every 48 h in rats. Behavior changes were observed for 30 min after every injection of PTZ.

RESULTIp injection of histidine or icv injection of clobenpropit inhibited the development of kindling induced by PTZ, presenting prolonged latency for myoclonic jerks and clonic generalized seizures and depressed seizure stages in a dose-dependent manner. H(3)receptor agonist, immepip, and histidine decarboxylase, alpha-fluoromethylhistidine reversed the ameliorating effect of clobenpropit on seizure development in a dose-dependent manner.

CONCLUSIONBrain histamine plays an important role in protection against myoclonic jerks and clonic generalized clonic seizures and its action may be via H(3)receptor.

Animals ; Brain ; physiology ; Chronic Disease ; Dose-Response Relationship, Drug ; Epilepsy ; chemically induced ; Histamine ; physiology ; Histidine ; pharmacology ; Imidazoles ; pharmacology ; Male ; Pentylenetetrazole ; pharmacology ; Piperidines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Thiourea ; analogs & derivatives ; pharmacology

OBJECTIVETo investigate the effects of clobenpropit and histidine on reinstatement of morphine-induced conditioned place preference (CPP) in rats.

METHODSThe persistence, extinction and reinstatement of morphine-induced CPP were established.In clobenpropit group three different doses of clobenpropit (2, 5 and 10 microg/rat, i.c.v.) were administered 15 min after morphine (1 mg/kg, i.p.) was injected. In histidine group histidine (100, 200, 500 mg/kg) was given 1 h prior to morphine treatment (1 mg/kg i.p).

RESULTThe CPP was reinstated by priming injection of 1 mg/kg morphine. Clobenpropit (5, 10 microg/rat) significantly inhabited the reinstatement by a priming dose of morphine-induced CPP compared with the morphine control group; histidine (100, 200, 500 mg/kg) significantly inhibited the reinstatement in a dose-dependent manner.

CONCLUSIONClobenpropit and histidine inhibit the revival of morphine-induced CPP in a dose dependent manner, indicating that endogenous histamine may inhibit relapse of morphine to some extent.

Animals ; Conditioning, Operant ; drug effects ; Histidine ; metabolism ; Imidazoles ; pharmacology ; Male ; Morphine Dependence ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Cell Surface ; antagonists & inhibitors ; Substance Withdrawal Syndrome ; physiopathology ; Thiourea ; analogs & derivatives ; pharmacology

AIMTo search for novel compounds with potent nNOS inhibitory activity for the treatment of Alzheimer's disease.

METHODSThe target compounds were obtained by introducing benzenealkyl groups into the structure of isothioureas. nNOS inhibitory activity assays were conducted for the target compounds.

RESULTSSixteen benzenealkyl isothiourea compounds (I1-16) were synthesized by three different synthetic methods from benzylamine (1) or (substituted) phenethylamine (2). Compounds I1-6 were synthesized from 1 or 2 by reaction with benzoyl isothiocyanate to form the corresponding benzoylthioureas 3 or 4, followed by hydrolysis with 10% sodium hydroxide solution, then S-alkylation with methyl iodide or ethyl iodide. I7-14 were synthesized from 1 or 2 by reaction with methyl isothiocyanate to form the corresponding 1, 3-disubstituted thioureas 7 or 8 which were S-alkylated with methyl iodide or ethyl iodide. I15 and I16 were synthesized from 2 by reaction with dimethyl cyanodithioimidocarbonate. The structures of compounds I1-16 were confirmed by MS, IR, 1HNMR and elementary analysis. The results of preliminary pharmacological test showed that all compounds possessed nNOS inhibitory activity, among which compounds I8, I12 and I14 had good activity.

CONCLUSIONCompounds I8, I12 and I14 showed superior pharmacological profiles to the control compound S-methyl-N-(4-methoxyphenyl) isothiourea. The IC50 values of compounds I8, I12 and I14 inhibiting nNOS were 8.13 x 10(-7) mol.L-1, 1.74 x 10(-7) and 2.23 x 10(-7) mol.L-1 respectively, and it is worth further studying.

Animals ; Cattle ; Cells, Cultured ; Hippocampus ; cytology ; enzymology ; Inhibitory Concentration 50 ; Molecular Structure ; Nerve Tissue Proteins ; antagonists & inhibitors ; metabolism ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Nitric Oxide Synthase Type I ; Structure-Activity Relationship ; Thiourea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

OBJECTIVETo define the effects of Astragalus membranaceus on the atrial dynamics and ANP secretion in the perfused beating rabbit atria.

METHODThe experiments have been done in isolated perfused beating rabbit atria. ANP was measured by radioimmunoassay in the atrial perfusate in real-time base.

RESULTA. membranaceus (2.0, 2.5, 3.0 g L(-1)) could increase atria stroke volume from (694.70 +/- 0.01) microL g(-1) (P<0.05) to (1,003.00 +/- 8.80) microL g(-1) (P<0.001); (1,120.00 +/- 17.71) microL g(-1) and (1,195.00 +/- 8.21) microL g(-1) (P<0.001), respectively, and its could difference increase atrial pulse pressure from (0.82 +/- 0.01) kPa to (0.86 +/- 0.01) kPa (P<0.01); (0.96 +/- 0.01) kPa (P<0.001) and (1.02 +/- 0.01) kPa (P<0.001), respectively; A. membranaceus obviously increased rabbit atrial dynamics with dose-dependent manner. Simultaneously, A. membranaceus inhibited ANP secretion. Nifedipine (1.0 micromol L(-1)), a L-type Ca2+ channel inhibitor, and KB-R 7943 (10.0 micromol L(-1)), an inhibitor of reversed Na+ -Ca2+ exchanger, blocked the effects of A. membranaceus-induced augmentation of atrial dynamics but failed to modulation the inhibition of A. membranaceus on ANP secretion.

CONCLUSIONA. membranaceus increases the atrial dynamics via Na+ -Ca2+ exchanger and L-type Ca2+ channel and negatively modulates ANP secretion in beating rabbit atria.

Animals ; Astragalus membranaceus ; chemistry ; Atrial Natriuretic Factor ; metabolism ; secretion ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Female ; Heart Atria ; drug effects ; metabolism ; secretion ; Male ; Myocardial Contraction ; drug effects ; Nifedipine ; pharmacology ; Rabbits ; Radioimmunoassay ; Thiourea ; analogs & derivatives ; pharmacology