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At least 19 recordsLinked to original sources
PubMed1986

Identification and molecular characterization of the isoquinoline rat intestinal binding site using 6,7-dimethoxy-4-(4'-amino-3'-[125I]iodobenzyl) isoquinoline.

The mechanism of the relaxant action of isoquinolines on smooth muscle is conjectural. In order to gain further insight into the intestinal action of isoquinolines, we have synthesized an isoquinoline derivative which can be radioiodinated, resulting in the obtention of a ligand with a high specific activity. 6,7-Dimethoxy-4-(4'-aminobenzyl) isoquinoline (DMABI) is an arylamine analogue of the most relaxating isoquinoline derivative, i.e., 6,7-dimethoxy-4-(4'-chlorobenzyl) isoquinoline. Its iodinated derivative, 6,7-dimethoxy-4-(4'-amino-3'-[125I]iodobenzyl) isoquinoline (125I-DMABI) binds reversibly to rat intestinal membranes. Binding is rapid, saturable, and temperature dependent. The binding of 125I-DMABI to intestinal membranes is competitively inhibited by identical concentrations of unlabeled DMABI or iodo-DMABI in the range between 10(-8) and 10(-5)M. Scatchard analysis indicates the existence of two classes of binding sites: a class with a low capacity (14 +/- 2 pmol/mg of protein) and a Kd = 0.10 +/- 0.02 microM, and a class with a high capacity (240 +/- 31 pmol/mg of protein) and a Kd = 8.0 +/- 1.1 microM. Specific binding of the radioiodinated ligand is inhibited by a variety of 4-benzyl isoquinolines and 1-benzyl isoquinolines. Structure-activity relationship demonstrates the primordial role of C-6 and C-7 methoxy groups and the important role of 4-benzyl on configuration related to the isoquinoline nucleus. A high significant correlation between competitive binding (Ki) and relaxant effect in rat intestine (IC50) is observed and strongly suggests that the isoquinoline-binding site mediates the pharmacologic response. Upon photolysis, this ligand incorporates irreversibly into rat intestinal membranes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography reveal a major 125I-DMABI-labeled protein with molecular weight of 36,000 and two minor proteins with molecular weights of 52,000 and 26,000. The labeling of these proteins is specific since it is completely abolished by 100 microM DMABI. Scanning of autoradiographs and integration of peaks show that the probe binds with the same apparent affinity to the three proteins. These findings indicate the utility of this novel high affinity radioiodinated probe as a tool for elucidating the mechanism of action of isoquinoline.

Animals↗
PubMed1975

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline.

By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).

Binding Sites↗
PubMed1975

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3(2H)-one and its interaction with deoxyribonucleic acids and poly(deoxyribonucleotides).

3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.

Animals↗
PubMed1994

Novel spirosuccinimide aldose reductase inhibitors derived from isoquinoline-1,3-diones: 2-[(4-bromo-2-fluorophenyl)methyl]-6- fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone and congeners. 1.

The high concentrations of plasma glucose formed during diabetic hyperglycemia rapidly translate into high levels of glucose in tissues where glucose uptake is independent of insulin. In these tissues that include the lens, retina, nerve, and kidney, this excess glucose enters the sorbitol (polyol) pathway. The first enzyme in this pathway, aldose reductase, reduces glucose to sorbitol. The diabetes-induced increased flux of glucose through the polyol pathway is believed to play an important role in the development of certain chronic complications of diabetes mellitus. Compounds that inhibit aldose reductase activity and block the flux of glucose through the polyol pathway prevent the development of neuropathy and nephropathy in diabetic animals and interrupt the progression of neuropathy in diabetic patients. Here we describe the preparation and characterization of novel aldose reductase inhibitors. These spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'-(2H)-tetrones, based on the isoquinoline-1,3-dione framework, were evaluated in vitro for their ability to inhibit glyceraldehyde reduction, using a partially purified bovine lens aldose reductase preparation, and in vivo for their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. Substitution at the N-2 position of the isoquinoline-1,3-dione framework with diverse structural substituents (i.e., aralkyl, benzothiazolylmethyl, methyl) produced several excellent series of ARIs. Optimization of these new series of spirosuccinimides through structure-activity relationship (SAR) studies, including analogy from other drug series (ponalrestat, zopolrestat), led to the design of the clinical candidate 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H ),3'- pyrrolidine]-1,2',3,5'(2H)-tetrone (41). Compound 41 exhibited exceptional oral potency in two animal models of diabetic complications, the 14-day galactose-fed and streptozocin-induced diabetic rats, with ED50 values for the sciatic nerve of 0.1 and 0.09 mg/kg/day, respectively. Both enantiomeric forms of 41 exhibited similar inhibitory activity in both in vitro and in vivo assays possibly due to their rapid interconversion. In an ex vivo experiment, the pharmacodynamic effect of 41 in the plasma of rats and dogs, after a single dose, appeared to be comparable to that of tolrestat.

Aldehyde Reductase↗
PubMed1990

Inhibition of monoamine oxidases A and B by simple isoquinoline alkaloids: racemic and optically active 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines.

A series of 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines were tested as substrates and/or inactivators of highly purified human monoamine oxidase A and B (MAO A and B). None were found to be a substrate for either enzyme, but many of these isoquinolines could selectively inhibit either MAO A or B. Stereoselective competitive inhibition of MAO A was found with the R enantiomer of all the stereoisomers tested, including salsolinol (Ki = 31 microM), salsoline (Ki = 77 microM), salsolidine (Ki = 6 microM), and carnegine (Ki = 2 microM). As a class, the 3,4-dihydro-isoquinolines were the most potent inhibitors tested (Ki = 2-130 microM), and the fully aromatic isoquinolines had intermediate activity (Ki = 17-130 microM) against MAO A. In contrast, only a few of these compounds markedly inhibited MAO B. 1,2,3,4-Tetrahydroisoquinoline, its 2-methyl derivative, and o-methylcorypalline gave apparent Ki values of 15, 1, and 29 microM, respectively, and two 3,4-dihydroisoquinolines (compounds 22 and 25) showed substantial inhibition of MAO B (Ki = 76 and 15 microM, respectively). These results support the concept that the topography of the inhibitor binding site differs in MAO A and B.

Alkaloids↗
PubMed1987

Characterization of solubilized isoquinoline binding sites from rat intestine using 6,7-dimethoxy 4-(4'-amino, 3'(125I)iodobenzyl)isoquinoline.

In rat tissues, the specific binding of 6,7-dimethoxy 4-(4'-amino, 3'(125I)iodobenzyl)-isoquinoline is distributed as follows: aorta greater than pancreas greater than liver greater than intestine greater than stomach greater than lung greater than skeletal muscle greater than heart greater than brain. In aorta and intestine 125I-DMABI is specifically covalently incorporated after direct u.v. photolabeling, in a major polypeptide of Mr 36,000 daltons, and a minor polypeptide of Mr 52,000 daltons. In intestine another smaller minor polypeptide of Mr 26,000 is observed. In intestine a variety of isoquinolines are tested for their ability to inhibit the covalent photo-incorporation of 125I-DMABI. Inhibitory potency is influenced by 6,7-substitutions, e.g. 6,7-dimethoxy, and by the presence of benzyl ring in C-1 and C-4 positions. Isoquinoline is much more potent than tetrahydroisoquinoline. 125I-DMABI intestinal binding site is solubilized using Triton X-100. Layered on Sephadex G-25 column, a high specific peak of radioactivity is eluted in the void volume of the column. The 125I-DMABI binding protein loaded onto a Sephacryl S-300 column is eluted as a single peak corresponding to a species with a Stokes radius of 43.5 A. The sedimentation coefficient of the 125I-DMABI binding protein is measured by ultracentrifugation of 5.5 S, using 5-20% sucrose gradient. The calculated molecular weight of the intestinal 125I-DMABI binding protein is estimated at 110,000 daltons.

Animals↗
PubMed2006

Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2-b]-3-benzazocines.

A series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1-b]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.

Azocines↗
PubMed2002

Novel syntheses of enantiopure hexahydroimidazo[1,5-b]isoquinolines and tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones via iminium cation cyclizations.

Condensations of chiral diamines 11a-c with benzotriazole and formaldehyde gave benzotriazolyl intermediates 12a-c; similar condensations of alpha-amino-amides 10a-c with benzotriazole and paraformaldehyde gave 14a-c. Subsequent treatment of 12a-c and 14a-c with AlCl(3) led to enantiopure tricyclic 1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolines 1a-c and 2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 15a-c, respectively, via Lewis acid promoted iminium cation cyclizations.

Cyclization↗
PubMed2006

The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one].

The pharmacology of two novel, trequinsin-like PDE3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one], has been investigated in a number of in vitro and in vivo assays. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 microM) and RPL565 (10 microM) (percentage control; 93 +/- 1.2 and 84.4 +/- 2.7, respectively). Contractile responses were suppressed for up to 12 h after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 inhibited, in a concentration-dependent manner, lipopolysaccharide-induced tumor necrosis factor alpha release from human monocytes [IC50; 0.52 microM (0.38-0.69) and 0.25 microM (0.18-0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC50; 0.46 microM (0.24-0.9) and 2.90 microM (1.6-5.4), respectively]. The inhibitory effect of these drugs in vitro was translated into anti-inflammatory activity in vivo. RPL554 (10 mg/kg) and RPL565 (10 mg/kg) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing RPL554 by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibited the recruitment of eosinophils to the airways. Exposure of conscious guinea pigs to inhalation of dry powder containing RPL554 (2.5%) and RPL565 (25%) in micronized lactose significantly inhibited histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period. Thus, RPL554 and RPL565 are novel, long-acting PDE 3/4 inhibitors exhibiting a broad range of both bronchoprotective and anti-inflammatory activities.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Differential inhibition by an antitumoral drug 10-[gamma-diethylaminopropylamino]-6-methyl-5H-pyrido[3',4': 4,5]pyrrolo [2,3-G]isoquinoline (BD-40), a pyrido-pyrrolo-isoquinoline derivative, of in vitro DNA synthesis catalyzed by various DNA polymerases.

The effects of BD-40, a pyrido-pyrrolo-isoquinoline analogue of ellipticines, and its 2-acetylated derivative (BD-84) and in vitro DNA synthesis catalyzed by purified preparations of various DNA polymerases were examined. The major conclusions are: (1) Both BD-40 and BD-84 strongly inhibit the DNA synthesis by DNA polymerase or reverse transcriptase with poly(rA).oligo(dT) as the template.primer. (2) Both compounds moderately inhibit the DNA synthesis by DNA polymerase alpha or E. coli DNA polymerase I with activated DNA. However, the DNA synthesis by DNA polymerase beta is resistant to inhibition by BD-40 and slightly sensitive to that by BD-84. (3) BD-84 is more inhibitory than BD-40 in DNA syntheses by various DNA polymerases except in those by DNA polymerase alpha and terminal deoxyneuclotidyltransferase to which both compounds are similarly inhibitory. (4) Kinetic analyses revealed that the observed inhibitions are due to competition between the drug or the drug-bound template.primer and the free template.primer for the same binding site of the enzyme.

Animals↗
PubMed1989

Renal vasodilators. The role of the 4-substituent in isoquinolin-3-ol cardiovascular agents: 4-ureido derivatives of isoquinolin-3-ol with selective renal vasodilator properties.

The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.

Animals↗
PubMed1977

Isoquinolines. 6. Potential central nervous system antitumor agents. Nitrogen mustards of 3-amino-4-(p-aminophenyl)isoquinoline.

A series of 3-amino-4-(p-aminophenyl)isoquinolines bearing the bis(2-chloroethyl)amino group was synthesized as potential CNS antitumor agents. Diol precursors 1e and 1f were prepared by the treatment of 1b and 1c with ethylene oxide. Diol precursors 5a-c and 9 were prepared by the treatment of 4a-c and 8 with diethanolamine. The reaction of these diols with SOCl2 yielded target mustards 10-15 which were evaluated in the intraperitoneal murine L1210 tumor. No intermediates or target mustards were active in this tumor system.

Alkylating Agents↗
PubMed2000

Synthesis and cytotoxic activity of carboxamide derivatives of benzimidazo[2,1-a]isoquinoline and pyrido[3',2':4,5]imidazo[2,1-a]isoquinoline.

A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepared, in order to study the biological effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogues were obtained by modifications to published chemistry. The 1-carboxamide analogue was obtained via a one-pot isocoumarin/isoquinolone conversion of 3-methylisocoumarin-8-carboxylic acid with o-phenylenediamine in buffered aqueous acid, which gave the required 1-acid. The compounds were evaluated in a panel of cell lines in culture. The 6-carboxamides, where the side chain is attached to one of the central rings, were not active, but the 1- and 11-carboxamides, where the side chain is attached to one of the terminal rings off the chromophore short axis, were reasonably cytotoxic (IC50s < 1 microM). Overall, the structure-activity relationships are broadly in line with those seen with other tri- and tetracyclic carboxamides, and are consistent with recent crystal structure studies of acridine-4-carboxamides bound to DNA. The most potent 1-carboxamide was highly active in vivo against s.c. colon 38 tumours in mice, providing a growth delay of 12 days.

Animals↗
PubMed1988

Studies on isoquinoline derivatives. IV. Synthesis and evaluation of the antimicrobial and antifungal activities of N2-arylidene-substituted 3-carbazoyl-isoquinolines.

2,4-Dimethyl-1-oxo-1,2-dihydro-3-carbazoyl-isoquinoline (II), 1-chloro-, 1-methoxy-3-carbazoyl-4-methylisoquinoline (VI, X) and a series of their hydrazonic derivatives have been synthesized and tested in vitro for antibacterial and antifungal activities. 1-(1-Chloro-4-methyl-3-isoquinolinoyl)-2-(5-nitro-2-furfurylide ne) hydrazine (VII h) proved to be the most effective in the series (MIC 0.78 micrograms/ml) and was more potent than furazolidone against several strains of S.aureus; the same compound also showed a moderate antifungal activity.

Anti-Bacterial Agents↗