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J M Cook

Publications and source records attributed to J M Cook.

At least 19 recordsLinked to original sources
PubMed1992

Predictive binding of beta-carboline inverse agonists and antagonists via the CoMFA/GOLPE approach.

The synthesis and affinities of six new 3-substituted beta-carbolines (6-10, 12) for the benzodiazepine receptor (BzR) are described. These analogs were used both to probe the dimensions of the hydrophobic pocket in the benzodiazepine receptor and to test the predictive ability of a previously reported 3D-QSAR regression model. Of the new analogs synthesized, the gamma-branched derivatives (isobutoxy, 7, IC50 = 93 nM; isopentoxy, 9, IC50 = 104 nM) display significantly higher affinity for the BzR than either the beta-branched (sec-butoxy, 6, IC50 = 471 nM; tert-butyl ketone, 12, IC50 = 358 nM) or delta-branched (isopentoxy, 8, IC50 = 535 nM) analogs. An exception to this rule is the gamma-branched 3-benzyloxy derivative 10 (IC50 > 1000 nM) which appears to have a chain length that is too long to be accommodated by the BzR. The standard error of prediction for these six new beta-carbolines using the original regression model is significantly lower than the standard error estimate of the cross validation runs on the training set, hence the predictions made using this model are much better than expected. In order to obtain more credible predictions, a new procedure called GOLPE (generating optimal linear PLS estimates) was used to eliminate irrelevant electrostatic and steric descriptors from the regression equation. A substantial reduction in the standard error estimate resulted. The predictions from this new regression equation were somewhat less accurate than the ones obtained with the original regression equation; however the standard error of prediction and the standard error estimate are in much closer agreement. Finally, to probe the effect that the quality of the steric and electrostatic potentials has on 3D-QSAR analyses, the semiempirical MNDO parallel PRDDOE geometries and Mulliken charges used in the original analyses were replaced with ab initio 3-21G parallel 6-31G* geometries and electrostatic potential fit charges. A modest decrease in the standard error estimate and increase in cross validated R2 resulted.

Animals↗
PubMed1992

Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogues of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones at benzodiazepine receptors.

Based on the topology of pyrazoloquinolinones 10-12, a series of 2-phenyl-2H-pyrazolo[4,3-c]isoquinolines 6a-d, 7a-d, 8, and 9 have been synthesized and evaluated for their ability to inhibit radioligand binding to benzodiazepine receptors (BzR). Modification of the hydrogen bonding donor and acceptor characteristics of the NH and C = O functionalities of the pyrazoloquinolinones 10-12 resulted in ligands with dramatically reduced affinities (IC50 much greater than 2 microM) for BzR. The low affinities of 6a-d, 7a-d, 8, and 9 are consistent with the involvement of the NH function present on diverse classes of inverse agonists (beta-carbolines, diindoles, and pyrazoloquinolinones) with a hydrogen bond acceptor site (A2) on the binding protein. Moreover, it supports the involvement of the carbonyl function of the pyrazoloquinolinones and the pyridine nitrogen atom of beta-carbolines and diindoles with a hydrogen bond donor site (H1). Finally, the results from this work indicate that a simultaneous interaction at both hydrogen bond donor (H1) and acceptor sites (A2) at BzR is required for high affinity binding of inverse agonists.

Animals↗
PubMed1992

Structure-function analysis of exotoxin A proteins with mutations at histidine 426.

Substitution of Tyr for His-426 of Pseudomonas aeruginosa exotoxin A results in a mutant protein with reduced ADP-ribosyltransferase activity (M. J. Wick and B. H. Iglewski, J. Bacteriol. 170:5385-5388, 1988). To investigate the role of His-426 in enzymatic activity, oligonucleotide-directed mutagenesis was used to construct mutant proteins encoding Ala, Glu, Gly, Lys, or Pro at position 426. The effect of these amino acid substitutions on ADP-ribosyltransferase activity was analyzed in 34,000-Da carboxy-terminal exotoxin A peptides (H426n peptides). ADP-ribosyltransferase activity of the H426n peptides fell within a range between 0.002 and 28% of wild-type levels of activity, suggesting that His-426 is required for full expression of enzymatic activity of exotoxin A. To investigate a possible catalytic function of His-426, the abilities of full-size (66,000-Da) wild-type exotoxin A and mutant proteins encoding either Ala-426 or Tyr-426 to hydrolyze NAD were compared by measuring NAD-glycohydrolase activity. This analysis revealed that exotoxin A encoding either Ala-426 or Tyr-426 expressed less than 1% of wild-type levels of NAD-glycohydrolase activity. Several criteria, including differential enzymatic activation properties and unique tryptic digestion patterns, revealed that the wild-type and mutant full-size proteins exhibit conformational differences. Our data suggest that His-426 plays a critical structural role in establishing the molecular architecture of the catalytic site in domain III and is important in orienting active-site residues in the cleft.

ADP Ribose Transferases↗
PubMed1992

Punishment of schedule-controlled behavior with beta-carboline injections: antagonism and comparisons with other compounds.

Squirrel monkeys were trained to press a key under a multiple schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). In the presence of the red stimulus lights (punishment component), the first response of each fixed-ratio produced either an i.v. injection of histamine [30.0-100.0 micrograms/kg/injection (inj)] or saline, accompanied by a 200-msec presentation of amber stimulus lights. Sessions in which histamine was injected alternated with sessions in which saline was injected. Another group of subjects was studied under identical schedule conditions except that electric shock was scheduled with the 200-msec stimulus light. During alternate sessions, electric shock at a high or low intensity with the stimulus, or the stimulus alone was scheduled. When performances stabilized, histamine or high intensity electric shock selectively suppressed responding in the punishment component; saline, low intensity electric shock or the stimulus light alone had no effects. Subsequently, different doses of histamine, I-nicotine, cocaine or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were substituted for histamine during single sessions. Histamine (17.8-100 micrograms/kg/inj), I-nicotine (32 micrograms/kg/inj) and beta-CCE (10-56 micrograms/kg/inj), but not cocaine (10.0-100.0 micrograms/kg/inj), produced a dose-related selective suppression of responding similar to that obtained with electric shock, suggesting that the drugs were functioning as punishers. Punishment by beta-CCE was antagonized with the benzodiazepine antagonist, flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons.

Acute i.m. injections of benzodiazepine receptor ligands were administered to baboons before 1-h observational sessions. The agonist midazolam produced sedative effects, the antagonist flumazenil produced no behavioral effects, the inverse agonist FG7142 produced tremor and the inverse agonist 3-carboethoxy-beta-carboline hydrochloride (beta CCE) produced tremor, vomiting, jerks and seizures. Co-administration of these drugs (midazolam + beta CCE, midazolam + flumazenil or flumazenil + beta CCE) produced a mutual antagonism of these effects. Compared to the non-dependent condition, in the diazepam-dependent condition (baboons maintained on 20 mg/kg per day diazepam) and withdrawn condition (dependent baboons tested during withdrawal), midazolam produced decreased sedative effects, flumazenil produced increased effects (i.e., tremor, vomiting and jerks), and beta CCE produced increased frequency of seizures. Taken together, these data suggest that (1) benzodiazepine receptor ligands lie on a continuum of behavioral activity, and (2) chronic diazepam administration alters the behavioral effects of these benzodiazepine ligands, producing a shift in the direction of the inverse agonist.

Animals↗
PubMed1991

Hyperparathyroidism presenting as an unusual cause of lower extremity gangrene.

Vascular surgeons are often consulted on the management of lower extremity ulcerations and gangrene which are commonly due to atherosclerotic arterial occlusive disease or to chronic venous insufficiency. The following report describes an unusual case of severe lower extremity cutaneous gangrene associated with secondary hyperparathyroidism and a review of the literature.

Amputation, Surgical↗
PubMed1991

Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors.

In order to employ rational drug design in the discovery of selective benzodiazepine receptor agonists and inverse agonists, pharmacophore/receptor models for both these activities must first be established. Recently, a pharmacophore for the inverse agonist site has been formulated employing the most recent receptor mapping techniques (22). The continuation of this approach to the pharmacophore for agonist ligands has permitted a definition of this site independently of the inverse agonist model. The agonist pharmacophore/receptor contains two hydrogen bond donating sites of interaction (H1 and H2) located about 6.5 A from each other, as well as three areas of lipophilic interaction (L1-L3). The areas L1 and L2 are critical for agonist activity; moreover, some ligands also require an interaction in a third lipophilic area termed L3. This is in agreement with previous work (12-23). In addition, an area of negative steric interaction (S1) between the ligand and receptor-binding protein is defined. In regard to the pharmacophore, it was established that the alignment rule for agonist beta-carbolines is different from that which elicits inverse agonist activity. Consideration of the pharmacophore has resulted in the synthesis of a new beta-carboline 16 which elicits agonist activity. This ligand 16 not only satisfied the requirements of the pharmacophore, but more importantly it elicited both anticonvulsant and anxiolytic activity, but was devoid of the myorelaxant/ataxic properties associated with the benzodiazepines.

Animals↗
PubMed1991

Thrombomodulin activity on human saphenous vein grafts prepared for coronary artery bypass.

Thrombomodulin, a membrane glycoprotein present on normal vascular endothelium, binds circulating thrombin and is important in protein C activation. These functions contribute to the nonthrombogenic nature of endothelium. Damage during harvest and ex vivo storage of vein grafts may result in dysfunction of this endothelial anticoagulant barrier and possibly contribute to early graft thrombosis. We studied the functional activity and antigenic expression of thrombomodulin on saphenous veins before (initial) and after (harvested) harvest and storage for coronary artery bypass grafting in 15 patients. Also, fresh saphenous vein was studied after mechanical endothelial stripping. After storage for 2.7 +/- 0.6 hours at room temperature in heparinized saline, thrombomodulin functional activity in harvested vein segments was 28% less than initial segments (p = 0.08). Endothelial stripping resulted in a 79% reduction in thrombomodulin activity compared with initial segments (p = 0.04). Immunohistochemical staining confirmed thrombomodulin antigen on vein grafts after harvest and storage, but not on segments stripped of endothelium. Thrombomodulin functional activity and antigenic expression on human saphenous vein grafts is not significantly changed by harvest and relatively short periods of storage at room temperature in heparinized saline.

Antigens↗
PubMed1991

Recurrent intracaval renal cell carcinoma: the role of intravascular ultrasonography.

The presence of extension into the vena cava does not preclude curative resection for extensive renal cell carcinomas. However, preoperative assessment of (1) the proximal extent of the tumor and (2) the degree of adherence within the vena cava is necessary to plan operative strategies. The following report describes the successful use of intravascular ultrasonography in the preoperative evaluation of a patient with recurrent renal cell carcinoma with vena caval extension.

Carcinoma, Renal Cell↗
PubMed1990

Affinity immunoblotting detection of serum monoclonal immunoglobulins reactive with glycosphingolipids.

The characterization of serum monoclonal IgM reactive with glycosphingolipid present in the nervous system is of major importance in patients with certain neuropathies. A rapid, sensitive and specific one-step method which permits such a characterization is described. Serum immunoglobulins separated by high resolution agarose electrophoresis are transferred to affinity filters (nitrocellulose sheets coated with glycolipids), and revealed with enzyme-tagged monospecific anti-immunoglobulin antibodies.

Antibodies, Monoclonal↗
PubMed1990

Current status of duplex Doppler ultrasound in the examination of the abdominal vasculature.

Duplex Doppler ultrasound has come to play a central role in the diagnosis of a broad spectrum of vascular diseases such as carotid artery occlusive disease and deep vein thrombosis. The role of duplex Doppler in the evaluation of intra-abdominal vascular disease remains unclear. This article summarizes the current status of duplex scanning in the investigation of the mesenteric arteries, the renal arteries, and the portal venous system. The examination is technically demanding, operator-dependent, time-consuming, and frequently unsatisfactory due to bowel gas, obesity, complex anatomy, or postoperative alterations in the normal anatomic patterns. Its advantages reside primarily in the absence of toxicity and in the generation of physiologic as well as anatomic information. In centers with the proper instrumentation and a skilled technician, duplex examination can be useful in the diagnosis and management of abdominal vascular disease and avoids the inherent dangers of contrast angiography.

Humans↗
PubMed1990

Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester.

The analogues 2, 3, 8a-c, 9, 13, and 14 of the beta-carboline 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (ZK-93423, 1) were synthesized in order to determine which functional groups are required for agonist activity exhibited by the parent compound 1 at the benzodiazepine receptor (BzR). The potencies of these compounds were evaluated in vitro and in vivo; the beta-carbolines 2, 8a-c, and 13 were found to exhibit high affinity (0.5-22 nM) for BzR, but in vivo studies demonstrated they were not anticonvulsant while analogues 8a and 8b antagonized the effects of diazepam. These results are in agreement with the model proposed for the pharmacophore of the agonist site (domain) of the BzR, which requires the interaction of two sites of electron density [N(2) and C(4)], a third at E+ (electrostatic or steric), and two of lipophilicity [C(3) and C(6)] of the ligand with the BzR protein (see Figure 1). The pharmacophore for the agonist site is derived from the structure-activity relationships of the benzodiazepines, pyrazoloquinolines, and the beta-carboline 1, and compared to interactions required for ligand inverse agonist activity.

Animals↗
PubMed1990

Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties.

A series of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 10-, and 12-substituted pyridodiindoles were synthesized and screened in vitro against [3H]diazepam for activity at the benzodiazepine receptor (BzR). In vitro, the 2-substituted pyridodiindoles were found to be the most potent (IC50 less than 10 nM) of this new class of BzR ligands. In vivo, 2-methoxypyridodiindole 19a (IC50 = 8 nM) was found to be the most potent partial inverse agonist (proconvulsant) of the series. The parent compound 2 (IC50 = 4 nM) was only slightly less potent. In addition, 2-hydroxypyridodiindole 21a (IC50 = 6 nM) was found to exhibit potent proconvulsant activity when administered as a prodrug derivative, pivaloyl ester 22. 2-Chloropyridodiindole 16a (IC50 = 10 nM) was devoid of preconvulsant activity; however, 16a was found to be the most potent antagonist of the anticonvulsant effects of diazepam in this class of BzR ligands. From the in vivo data available, substitution on ring E of 2 with electron-withdrawing groups results in antagonists at BzR, while replacement of hydrogen at C-2 with electron-releasing groups provides enhanced inverse agonist activity. The pyridodiindoles were used as "templates" for the formulation of a model of the inverse agonist/antagonist active site of the BzR. The proposed model consists of a hydrogen bond acceptor site (A1) and a hydrogen bond donor site (D2) disposed 6.0-8.5 A from each other on the receptor protein. The hydrogen-bonding sites are believed to be located at the base of a narrow cleft. A large lipophilic pocket at the mouth of the narrow cleft serves to direct molecules into the binding site, while the presence of a small lipophilic pocket permits substitution only at position 2 of the pyridodiindole nucleus for maximum binding potency.

Animals↗
PubMed1990

Traumatic left renal artery stenosis managed with splenorenal bypass: case report.

Splenorenal arterial bypass is a well established technique for the treatment of left renal artery occlusive disease. The following is a case report of the use of splenorenal bypass in the management of concomitant traumatic left renal artery intimal dissection and splenic laceration. Arteriographic and intraoperative findings are presented as well as a review of pertinent literature.

Humans↗