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P Abraham

Publications and source records attributed to P Abraham.

At least 127 records · Page 7Linked to original sources
PubMed1996

Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs.

New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkene analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.

Animals↗
PubMed1996

Synthesis, ligand binding, and quantitative structure-activity relationship study of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes: evidence for an electrostatic interaction at the 2 beta-position.

A set of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2 beta-carbomethoxy group. Several of the compounds showed high affinity and selectivity for the dopamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure-activity relationship study, the 3 beta-(4'-chlorophenyl)-2 beta-(3'-phenylisoxazol-5-yl)tropane (5d) emerged as the most potent and selective compound. The binding data for 2 beta-heterocyclic tropanes were found to show a high correlation with molecular electrostatic potential (MEP) minima near one of the heteroatoms in the 2 beta-substituents. In contrast, low correlations were found for other MEP minima near the 2 beta-substituent as well as for calculated log P or substituent volume. These quantitative structure-activity relationship studies are consistent with an electrostatic contribution to the binding potency of these WIN 35,065-2 analogs at the DAT.

Animals↗
PubMed1996

Existence of a high pressure zone at the rectosigmoid junction in normal Indian men.

PURPOSE: A hypertonic, electrically hyperactive segment has been described in the rectosigmoid region mainly in constipated persons. Anatomic or manometric evidence to satisfy the criteria for a sphincter here is, however, inconclusive. We evaluated the pressure profile of the rectosigmoid region in normal Indian men. METHODS: Fifteen male volunteers with regular bowel habits were studied. Rectosigmoid manometry (1 cm station pull-through) was done in the fasting state using a water-perfused system and three-lumen catheter with radially oriented recording ports 5 cm apart. RESULTS: Eight volunteers had a zone of high pressure. Proximal extent of this zone was identified as the station with a rise in basal pressure of at least 10 mmHg over the previous station. A further rise of at least 10 mmHg in subsequent distal stations was considered essential for defining the existence of the zone. This zone had a median length of 3 cm, with midpoint at median 18 cm from the anal verge and median highest pressure of 36 mmHg. There was no antegrade pressure gradient across the zone; rectal pressures were higher than those in the sigmoid in 12 of 15 volunteers. CONCLUSIONS: Approximately one-half of normal Indian men with regular bowel habits have a high pressure zone in the rectosigmoid region. The role of diet or defecation posture in its etiology and its effect on bowel habit need to be studied.

Adult↗
PubMed1996

Synthesis and in vivo studies of a selective ligand for the dopamine transporter: 3 beta-(4-[125I]iodophenyl) tropan-2 beta-carboxylic acid isopropyl ester ([125I]RTI-121).

A selective ligand for the dopamine transporter 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [125I]RTI-121 was obtained in good yield (86 +/- 7%, n = 3) with high radiochemical purity (> 99%) and specific radioactivity (1210-1950 mCi/mumol). After i.v. administration of [125I]RTI-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles > > cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling. Specific in vivo binding in striatum and olfactory tubercles was saturable, and was blocked by the dopamine transporter ligands GBR 12,909 and (+/-)-nomifensine. By contrast, binding was not reduced by paroxetine, a serotonin transporter inhibitor, or desipramine, a norepinephrine transporter inhibitor. A variety of additional drugs having high affinities for recognition sites other than the neuronal dopamine transporter also had no effect. The [125I]RTI-121 binding in striatum and olfactory tubercles was inhibited by d-amphetamine in dose-dependent fashion. Nonmetabolized radioligand represents 85% of the signal observed in extracts of whole mouse brain. Thus, [125I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo.

Amphetamine↗
PubMed1996

Ankle to arm index following maximal exercise in normal subjects and athletes.

Recent reports have suggested that minor arterial lesions can be responsible for claudication in athletes occurring only during maximal exercise. Ankle to arm index measurements (AAI) prove the arterial origin of this claudication, but little is known about the normal response of AAI to maximal exercise. Therefore, we studied the response of AAI to maximal exercise in trained and untrained normal subjects. AAI and heart rate (HR) were recorded at rest and following maximal exercise on a cycle ergometer in 15 untrained (VO2 = 41.5 +/- 4.0 ml.kg-1.min-1) and 15 trained (VO2 = 58.4 +/- 2.8 ml.kg-1.min-1) volunteers. All subjects were without known peripheral arterial disease. At rest, AAI was 1.08 +/- 0.08 in untrained subjects and 1.15 +/- 0.05 in trained subjects (P < 0.05). HR was 73.9 +/- 11.0 in untrained subjects and 57.1 +/- 8.3 in trained subjects (P < 0.05). Following exercise, AAI decreased during the first minutes of recovery in all subjects, with a significant difference between untrained and trained subjects. Although untrained subjects sustained a lower workload than trained subjects, at 1 min following exercise AAI was 0.70 +/- 0.06 in untrained versus 0.8 +/- 0.08 in trained subjects (P < 0.05). No difference in AAI to HR relationships was noted between untrained and trained subjects. In conclusion, we suggest that AAI should be interpreted with regard to HR at the end of maximal exercise and we project normal results for the AAI to HR relationships following maximal exercise.

Adolescent↗
PubMed1996

Hepatic perfusion index in portal hypertension of cirrhotic and non-cirrhotic aetiologies.

The hepatic perfusion index (HPI), the ratio of hepatic arterial to total liver blood flow, was determined by radionuclide angiography in 28 subjects with normal livers and 62 patients with portal hypertension of various aetiologies. The latter group comprised 50 patients with cirrhosis (14 Child class A, 20 Child class B, 16 Child class C) and 12 patients with non-cirrhotic portal hypertension (7 non-cirrhotic portal fibrosis, 5 extrahepatic portal venous obstruction). The mean (+/- S.D.) HPI was significantly higher among the patients with cirrhosis (Child class A, 53.9 +/- 18.1; Child class B, 65.6 +/- 29.4; Child class C, 78.6 +/- 33.5) and non-cirrhotic portal hypertension (54.9 +/- 17.7) compared with the subjects with normal livers (35.6 +/- 10.5). The patients with non-cirrhotic portal hypertension had a mean value similar to that of the cirrhotic patients in Child class A. A higher HPI was associated with worsening liver status. We conclude, therefore, that the HPI will be high in portal hypertension irrespective of aetiology and a rise in the HPI may indicate a deterioration in the condition of the liver.

Hepatic Artery↗
PubMed1996

Ankle to arm index response to exercise and heat stress in healthy subjects.

Ankle to arm index (AAI) defined as the ratio of ankle systolic blood pressure (ASBP), to brachial systolic blood pressure is largely used in the study of lower extremity arterial disease (LEAD). To study the hypothesis of the shunt of blood away from the skin as the explanation of AAI decrease in exercise, we studied the AAI and ASBP responses to an increase in cardiac output originating from an increase either in muscle blood flow (exercise) or in cutaneous blood flow (thermal stress). Brachial systolic pressure, ankle systolic pressure and heart rate (HR) were measured in 9 healthy subjects at rest, during heart thermal stress and following maximal exercise on a cycle ergometer. Compared to resting values, AAI decreased in all subjects from 1.05 +/- 0.07 to 0.75 +/- 0.07 (P < 0.05) 1 min following exercise and from 1.08 +/- 0.07 to 0.94 +/- 0.05 (P < 0.05) during heat stress. On the other hand, HR increased from 72.8 +/- 12.2 to 112.4 +/- 19.6 (P < 0.05) min following exercise and from 75.5 +/- 13.6 to 96.8 +/- 15.3 (P < 0.05) during heat stress. Since a comparable relation exists between AAI and HR in thermal stress and exercise, we suggest that the decrease in AAI in normal subjects following exercise is due to turbulences at high flow levels, rather than the shunting of blood to active muscles in exercise.

Adult↗
PubMed1996

Blood glutathione concentrations in a large-scale human study.

Little is known about the variability of blood glutathione (GSH) in human subjects. Thus, we wanted to develop and validate a rapid method for measuring GSH concentrations in whole blood and apply this method to ascertain the variation of GSH in a large-scale study of free-living adults. The assay was highly sensitive (detection limit < 5 pmol) and precise, with an interassay variation of 2.3% and a sampling variation of 3.6%. Applying this method to screen 715 adults, we observed a threefold range of GSH concentrations, with a mean of 1.02 mmol/L and CV of 17%. GSH concentrations were 8-10% greater in smokers than in nonsmokers (P < 0.001). Although we observed no sex differences for GSH, GSH/hemoglobin ratios were 8-18% greater in women < 55 years old than in older subjects (P < 0.05). The results presented here validate the use of this method for large-scale human studies and provide information on the variation and normal values of blood GSH in adults.

Adult↗
PubMed1996

Long-term stability of blood glutathione and cysteine in humans.

Glutathione (GSH) availability is an important factor in the maintenance of health. Accordingly, blood GSH has been proposed as an indicator of health status. To validate the use of blood GSH in population studies, we investigated the long-term intraindividual variation of blood GSH and cyst(e)ine (Cys and cystine) concentrations in healthy adults. In a longitudinal study of 10 subjects, GSH and cyst(e)ine were measured in blood samples collected weekly over 8 months. The average within-person CV for GSH was only 9.1% compared with an observed interindividual CV of 20%. Blood cyst(e)ine was more variable within individuals (mean CV 14.7%) than GSH, whereas the interindividual CV for cyst(e)ine was lower (8.6%). The results demonstrate the stability of blood GSH in free-living subjects and the utility of GSH measurements as an indicator of long-term GSH status.

Adult↗
PubMed1995

Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter.

Several 2 beta-carboxylic acid ester and amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3 beta-(4'-methylphenyl)- and 3 beta-(4'-chlorophenyl)tropane-2 beta-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3 beta-(4'-chlorophenyl)tropane-2 beta-N-morpholinocarboxamide as well as the 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-N- pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N-dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3 beta-(4'-iodophenyl)-tropane-2 beta-carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.

Amides↗
PubMed1995

Mapping dopamine transporters in the human brain with novel selective cocaine analog [125I]RTI-121.

The novel cocaine analog RTI-121 [3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid isopropyl ester] was evaluated as a probe for the in vitro labeling and localization of the dopamine transporter in the human brain. Saturation binding experiments conducted in sucrose-phosphate buffer (10 mM sodium phosphate, pH 7.4, 0.32 M sucrose) revealed high- and low-affinity binding components with affinity values (KD) of 0.25 +/- 0.04 and 4.9 +/- 1.6 nM (mean +/- SE) and densities (Bmax) of 56.8 +/- 13.8 and 147.7 +/- 23.4 pmol/g tissue, respectively. In contrast, when saturation binding experiments were performed in phosphate-buffered saline (10 mM Na2HPO4, 1.8 mM KH2PO4, 136 mM NaCl, 2.8 mM KCl, 10 mM NaI, pH 7.4), a 9-fold decrease in the density of the low-affinity component was noted, suggesting that the low-affinity RTI-121 binding site is associated with the region of the transporter involved in the ionic dependence of substrate recognition and/or uptake. The rank order of potency for inhibition of [125I]RTI-121 binding to human caudate membranes demonstrates that the radioligand selectively labels the dopamine transporter (GBR 12909 > RTI-121 > mazindol > nomifensine > (-) cocaine > desipramine > citalopram). Autoradiographic mapping of [125I]RTI-121 revealed very high densities of cocaine recognition sites over areas known to be rich in dopaminergic innervation, including the caudate, putamen, and nucleus accumbens. Moderate densities were also observed over the substantia nigra and the ventral tegmental area. Low-to-background labeling of [125]RTI-121 was seen throughout the cerebral cortex, amygdaloid nuclei, globus pallidus, and thalamus. In comparison with the autoradiographic distribution of the cocaine analogs [3H]WIN 35,428 (or CFT) and [125I]RTI-55 (or beta-CIT), the labeling pattern for [125I]RTI-121 was more restricted. These studies demonstrate that [125I]RTI-121 labels dopamine-rich brain regions with greater selectivity than other currently available cocaine analogs, which makes it a potentially superior imaging probe for mapping the dopamine transporter in the human brain.

Adult↗