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1.
J Inorg Biochem ; 186: 60-69, 2018 09.
Article in English | MEDLINE | ID: mdl-29857172

ABSTRACT

The misfolding and fibrillation of human islet amyloid polypeptide (hIAPP) is related to the pathologic process of type II diabetes mellitus (T2DM). The inhibitors of hIAPP aggregation include aromatic organic molecules, short peptides, and metal complexes. Vanadium complexes have been applied for the treatment of diabetes since the 19th century. However, the antidiabetes mechanism remains unclear. In this work, we used four Schiff base oxidovanadium(IV) complexes, namely VO(bhbb)·H2O (1, and ligand 1 H2bhbb, 2-(5-bromo-2-hydroxylbenzylideneamino) benzoic acid), VO(nhbb)·H2O (2, and lignad 2 H2nhbb, 2-(5-nitro-2-hydroxylbenzylideneamino) benzoic acid), VO(cpmp)2 (3, and ligand 3 Hcpmp, 4-chloro-2-(phenylimino) methyl) phenol), and VO(bpmp)2 (4, and ligand 4 Hbpmp, 4-bromo- 2-(phenylmino) methyl) phenol) to inhibit the fibril formation of hIAPP and reduce peptide-induced cytotoxicity. Results indicated that the four Schiff base oxidovanadium complexes effectively impeded hIAPP aggregation and disaggregated mature fibrils into monomers or oligomers. These V complexes also decreased hIAPP-induced cytotoxicity. Among the four V complexes, 1 is a promising candidate metallodrug considering its inhibitory effect, disaggregation ability, regulation of peptide-induced cytotoxicity, and binding affinity to the peptide. Our research provides a new outlook for the design of oxidovanadium complexes as effective inhibitors of hIAPP against T2DM.


Subject(s)
Antidiarrheals , Islet Amyloid Polypeptide/antagonists & inhibitors , Islet Amyloid Polypeptide/chemistry , Protein Aggregates , Vanadates/chemistry , Antidiarrheals/chemical synthesis , Antidiarrheals/chemistry , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Humans , Schiff Bases/chemical synthesis , Schiff Bases/chemistry
2.
Carbohydr Polym ; 194: 311-318, 2018 Aug 15.
Article in English | MEDLINE | ID: mdl-29801844

ABSTRACT

The sequential optimization of carboxymethylation of pectin by Plackett-Burman (PB) design and response surface methodology (RSM) was reported in this study. PB design was employed to screen the six process variables (ethanol concentration, liquid-polymer ratio, NaOH concentration, CAA concentration, temperature and time). Central composite design (CCD) was used to study the interaction effects of ethanol concentration, NaOH concentration, CAA concentration and time on degree of substitution (DS) in carboxymethylated pectin (CMP). Maximum DS value of 0.496 was predicted at ethanol concentration (80%), NaOH concentration (38%), CAA concentration (8.5%) and time (60 min). The synthesized CMP was characterized by FT-IR, XRD, TGA and viscometer. Results of FTIR, XRD and TGA confirmed the modification made in the pectin polymer and highly methylated. Faster release of 5-FU drug was observed with CMP-chitosan nanoparticles as compared to pectin-chitosan nanoparticles and the drug release followed zero order kinetics model.


Subject(s)
Antidiarrheals/chemistry , Drug Delivery Systems , Fluorouracil/chemistry , Pectins/chemistry , Antidiarrheals/chemical synthesis , Methylation , Particle Size , Pectins/chemical synthesis , Surface Properties
3.
Biomed Res Int ; 2016: 3167085, 2016.
Article in English | MEDLINE | ID: mdl-27777944

ABSTRACT

Introduction. Microcos paniculata is traditionally used for treating diarrhea, wounds, cold, fever, hepatitis, dyspepsia, and heat stroke. Objective. To investigate the qualitative phytochemical constituents of hydromethanol (HMPB) and petroleum benzene extract of Microcos paniculata barks (PBMPB) and to evaluate their antinociceptive and antidiarrheal activities. Methods. Phytochemical constituents and antinociceptive and antidiarrheal activities were determined and evaluated by different tests such as Molisch's, Fehling's, Mayer's, Wagner's, Dragendorff's, frothing, FeCl3, alkali, Pew's, and Salkowski's test, general test of glycosides, Baljet and NH4OH test, formalin-induced paw licking, acetic acid-induced writhing, tail immersion, and hot plate tests, and castor oil and MgSO4 induced diarrheal tests. Results. These extracts revealed the presence of saponins, flavonoids, and triterpenoids and significantly (⁎P < 0.05, versus control) reduced paw licking and abdominal writhing of mice. At 30 min after their administration, PBMPB revealed significant increase in latency (⁎P < 0.05, versus control) in tail immersion test. In hot plate test, HMPB and PBMPB 200 mg/kg showed significant increase in response latency (⁎P < 0.05, versus control) at 30 min after their administration. Moreover, both extracts significantly (⁎P < 0.05, versus control) inhibited percentage of diarrhea in antidiarrheal models. Conclusion. Study results indicate that M. paniculata may provide a source of plant compounds with antinociceptive and antidiarrheal activities.


Subject(s)
Analgesics/administration & dosage , Antidiarrheals/administration & dosage , Diarrhea/drug therapy , Methanol/chemistry , Pain/drug therapy , Plant Extracts/administration & dosage , Analgesics/chemical synthesis , Animals , Antidiarrheals/chemical synthesis , Benzene/chemistry , Diarrhea/diagnosis , Diarrhea/physiopathology , Drug Evaluation, Preclinical/methods , Female , Male , Malvaceae/chemistry , Mice , Pain/diagnosis , Pain/physiopathology , Pain Measurement/drug effects , Petroleum , Phytotherapy/methods , Plant Bark/chemistry , Plant Extracts/chemistry , Treatment Outcome , Water/chemistry
4.
Org Biomol Chem ; 14(36): 8503-19, 2016 Sep 28.
Article in English | MEDLINE | ID: mdl-27541268

ABSTRACT

Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 µM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 µM, 0.69 ± 0.07 µM and 0.66 ± 0.05 µM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.


Subject(s)
Antidiarrheals/pharmacology , Loperamide/pharmacology , Myeloid-Lymphoid Leukemia Protein/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Antidiarrheals/chemical synthesis , Antidiarrheals/chemistry , Dose-Response Relationship, Drug , Humans , Loperamide/chemical synthesis , Loperamide/chemistry , Models, Molecular , Molecular Structure , Myeloid-Lymphoid Leukemia Protein/metabolism , Proto-Oncogene Proteins/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
5.
Peptides ; 31(8): 1617-24, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20434497

ABSTRACT

Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)), a tetrapeptide present in the enzymatic digest of bovine beta-casein, is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 1-3. Two of the obtained analogs, [Dmt(1), D-Ala(2), D-1-Nal(3)]morphiceptin and [Dmt(1), D-NMeAla(2), D-1-Nal(3)]morphiceptin (Dmt-2',6'-dimethyltyrosine and d-1-Nal-3-(1-naphthyl)-D-alanine)) displayed very high mu-receptor affinity, resistance to enzymatic degradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test after intracerebroventricular but not intravenous administration, which indicated that they could not cross the blood-brain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility. We report that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception, inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome.


Subject(s)
Endorphins/chemistry , Endorphins/chemical synthesis , Endorphins/pharmacology , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Peripheral Nervous System Agents/chemical synthesis , Peripheral Nervous System Agents/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacology , Animals , Antidiarrheals/chemical synthesis , Antidiarrheals/chemistry , Antidiarrheals/metabolism , Antidiarrheals/pharmacology , Colon/drug effects , Colon/metabolism , Drug Design , Drug Stability , Endorphins/administration & dosage , Endorphins/metabolism , Female , Gastrointestinal Motility/drug effects , In Vitro Techniques , Injections, Intraperitoneal , Injections, Intraventricular , Ligands , Male , Mice , Mice, Inbred C57BL , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Neurotransmitter Agents/chemistry , Neurotransmitter Agents/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Pain Measurement , Peripheral Nerves/drug effects , Peripheral Nervous System Agents/chemistry , Peripheral Nervous System Agents/metabolism , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
7.
Chem Biol Drug Des ; 67(6): 432-6, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16882318

ABSTRACT

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.


Subject(s)
Antidiarrheals/chemical synthesis , Antidiarrheals/pharmacology , Diarrhea/drug therapy , Loperamide/analogs & derivatives , Thiazolidinediones/chemical synthesis , Animals , Antidiarrheals/chemistry , Antidiarrheals/therapeutic use , Castor Oil/toxicity , Diarrhea/chemically induced , Loperamide/therapeutic use , Loperamide/toxicity , Mice , Models, Molecular , Naloxone/pharmacology , Structure-Activity Relationship , Thiazolidinediones/chemistry
8.
Arch Pharm (Weinheim) ; 338(11): 548-55, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16281304

ABSTRACT

The synthesis by microwave irradiation and the biological results of novel benzotriazinone and saccharine derivatives with potential antidiarrhoeal activity is described. Conventional and microwave heatings were compared for the reactions. Good yields and short reaction times are the main advantages of our synthetic route. Among the tested compounds, compound 12 inhibited motility both in in-vitro and in-vivo tests.


Subject(s)
Antidiarrheals/chemical synthesis , Gastrointestinal Transit/drug effects , Microwaves , Saccharin/analogs & derivatives , Saccharin/chemical synthesis , Triazines/chemical synthesis , Animals , Antidiarrheals/chemistry , Antidiarrheals/pharmacology , Chemistry, Pharmaceutical , Electric Stimulation , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Mice , Mice, Inbred ICR , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Saccharin/pharmacology , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacology
9.
J Pharm Sci ; 90(11): 1907-14, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11745748

ABSTRACT

The purpose of this study was to evaluate the potential of polycarbophil-cysteine conjugates (PCP-Cys) as an oral excipient to protect leucine enkephalin (leu-enkp) from enzymatic degradation by the intestinal mucosa. Cysteine was covalently linked to polycarbophil by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC). Inhibitory activity was tested towards isolated aminopeptidase N and excised intact pig intestinal mucosa, with native mucus. Aminopeptidase N activity was assayed spectrophotometrically using L-leucine p-nitroanilide (leu-pNA) as a synthetic substrate and against the model peptide drug leu-enkp, by high-performance liquid chromatography (HPLC). Free cysteine at 6.3 and 63 microM (pH 6) significantly (p < 0.05) inhibited aminopeptidase N activity, and PCP-Cys (0.25% w/v, pH 6) had a significantly (p < 0.05) greater inhibitory effect than PCP on the aminopeptidase N activity towards both substrates. PCP-Cys completely protected leu-enkp against aminopeptidase N activity over a 2-h incubation period, whereas 83 +/- 4 and 60 +/- 7% remained stable in the presence of PCP and buffer only, respectively. Leu-enkp in the absence and presence of PCP (0.25% w/v) at pH 6 was completely digested by the intact intestinal mucosa at the 60- and 90-min incubation time points, respectively, whereas in the presence of PCP-Cys (0.25% w/v, pH 6) 11 +/- 3.5% of leu-enkp remained at the 120-min time point. Thiolation of PCP increased the stability of leu-enkp against the enzymatic degradation by aminopeptidase N and the intact intestinal mucosa, identifying a promising new excipient for peroral delivery of peptides.


Subject(s)
Acrylic Resins/pharmacology , Antidiarrheals/pharmacology , CD13 Antigens/antagonists & inhibitors , Intestinal Mucosa/drug effects , Sulfhydryl Reagents/metabolism , Acrylic Resins/chemical synthesis , Animals , Antidiarrheals/chemical synthesis , CD13 Antigens/metabolism , Cysteine/chemical synthesis , Cysteine/metabolism , Cysteine/pharmacology , Intestinal Mucosa/enzymology , Intestinal Mucosa/ultrastructure , Microvilli/drug effects , Microvilli/enzymology , Microvilli/ultrastructure , Sulfhydryl Reagents/chemical synthesis , Sulfhydryl Reagents/pharmacology , Swine
10.
J Med Chem ; 44(2): 232-44, 2001 Jan 18.
Article in English | MEDLINE | ID: mdl-11170633

ABSTRACT

The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.


Subject(s)
Antidiarrheals/chemical synthesis , Cyclohexylamines/chemical synthesis , Spermine/analogs & derivatives , Spermine/chemical synthesis , Administration, Oral , Animals , Antidiarrheals/chemistry , Antidiarrheals/pharmacology , Antidiarrheals/toxicity , Castor Oil , Cyclohexylamines/chemistry , Cyclohexylamines/pharmacology , Cyclohexylamines/toxicity , Diarrhea/chemically induced , Diarrhea/drug therapy , Dogs , Female , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Rats , Rats, Sprague-Dawley , Spermine/chemistry , Spermine/pharmacology , Structure-Activity Relationship , Tissue Distribution , Toxicity Tests, Acute
11.
Farmaco ; 52(4): 237-41, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9241829

ABSTRACT

A series of aryl-hydroxy-piperidinoalkyl-thiazolidinones was synthesized and evaluated to inhibit castor oil-induced diarrhea in mice. The dose dependent antidiarrheal activity of the most active compound 2-(p-nitrophenyl)-3-¿2-[(4-(p-chlorophenyl)-4-hydroxy)piperidino]ethyl]- 1, 3-thiazolidin-4-one (6) was counteracted by naloxone, resulting comparable with that of loperamide, a mu opiate agonist.


Subject(s)
Antidiarrheals/pharmacology , Piperidines/pharmacology , Thiazoles/pharmacology , Animals , Antidiarrheals/chemical synthesis , Male , Mice , Molecular Structure , Piperidines/chemical synthesis , Thiazoles/chemical synthesis
12.
J Med Chem ; 39(13): 2461-71, 1996 Jun 21.
Article in English | MEDLINE | ID: mdl-8691443

ABSTRACT

The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.


Subject(s)
Antidiarrheals/chemical synthesis , Spermine/analogs & derivatives , Animals , Antidiarrheals/chemistry , Antidiarrheals/metabolism , Antidiarrheals/pharmacology , Biological Transport , Castor Oil , Cell Division/drug effects , Computer Simulation , Diarrhea/chemically induced , Diarrhea/prevention & control , Drug Design , Female , Kidney/metabolism , Leukemia L1210 , Liver/metabolism , Male , Mice , Models, Chemical , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Spermine/chemical synthesis , Spermine/chemistry , Spermine/metabolism , Spermine/pharmacology , Tumor Cells, Cultured
13.
J Med Chem ; 33(2): 614-26, 1990 Feb.
Article in English | MEDLINE | ID: mdl-1967650

ABSTRACT

Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.


Subject(s)
Adrenergic alpha-Agonists/chemical synthesis , Antidiarrheals/chemical synthesis , Gastrointestinal Motility/drug effects , Imidazoles/chemical synthesis , Receptors, Adrenergic, alpha/drug effects , Adrenergic alpha-Agonists/pharmacology , Animals , Blood Pressure/drug effects , Blood-Brain Barrier , Chemical Phenomena , Chemistry , Cholera Toxin/pharmacology , Dogs , Imidazoles/pharmacology , In Vitro Techniques , Intestinal Absorption/drug effects , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Thermodynamics
14.
J Med Chem ; 31(1): 138-44, 1988 Jan.
Article in English | MEDLINE | ID: mdl-2891854

ABSTRACT

Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).


Subject(s)
Adrenergic alpha-Agonists/chemical synthesis , Antidiarrheals/chemical synthesis , Guanidines/chemical synthesis , Hydrazones/chemical synthesis , Adrenergic alpha-Agonists/pharmacology , Animals , Cholera Toxin/toxicity , Female , Guanidines/pharmacology , Hydrazones/pharmacology , Ileum/drug effects , Ileum/metabolism , In Vitro Techniques , Indicators and Reagents , Jejunum/drug effects , Jejunum/metabolism , Male , Rabbits , Rats , Structure-Activity Relationship
15.
J Med Chem ; 19(10): 1221-5, 1976 Oct.
Article in English | MEDLINE | ID: mdl-994153

ABSTRACT

A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.


Subject(s)
Amines/chemical synthesis , Antidiarrheals/chemical synthesis , Amines/pharmacology , Analgesics/chemical synthesis , Animals , Gastrointestinal Motility/drug effects , Male , Mice , Reaction Time/drug effects , Structure-Activity Relationship
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