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Biomedical subjects

J Ellingboe

Publications and source records attributed to J Ellingboe.

At least 19 recordsLinked to original sources
PubMed2001

(4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists.

In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.

Adrenergic beta-Agonists↗
PubMed2001

New oxadiazolidinedione derivatives as potent and selective human beta3 agonists.

As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

2,4-Thiazolidinediones as potent and selective human beta3 agonists.

Methylsulfonamide substituted 2,4-thiazolidinedione 22c is a potent (EC50=0.01 microM, IA=1.19) and selective (more than 110-fold over beta1 and beta2 agonist activity) beta3 agonist. This compound has also been proven to be active and selective in an in vivo mode.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human beta(3) agonists.

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human beta(3) agonists with low affinities for beta(1)- and beta(2)-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs.

Adrenergic beta-3 Receptor Agonists↗
PubMed1999

Prodrugs of CL316243: a selective beta3-adrenergic receptor agonist for treating obesity and diabetes.

CL316243 is a highly selective and potent beta3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.

Adrenergic beta-Agonists↗
PubMed1994

Effects of aporphine isomers on rat prolactin.

S(+)-aporphines are partial agonists at D2 dopamine receptors. High selectivity of anti-dopaminergic action in limbic vs. extrapyr amidal regions of rat brain and lack of induction of dopaminergic supersensitivity have suggested their potential as atypical antipsychotic drugs. Now, in testing for effects on circulating prolactin, a typical D2 antagonist haloperidol elevated, and potent agonist R(-)-11-hydroxy-N-propylnoraporphine lowered, serum prolactin levels in gentled male rats, while S(+)-N-propylnorapomorphine and its 11-monohydroxy analog had little or no effect, even at high doses. Lack of hyperprolactinemia adds to characteristics of S(+)-aporphines that are desirable in improved antipsychotics.

Animals↗
PubMed1992

Buprenorphine attenuates the effects of cocaine on adrenocorticotropin (ACTH) secretion and mood states in man.

Adrenocorticotropin (ACTH) levels in plasma increased rapidly to 105% above baseline within 5 minutes after intravenous injection of cocaine (30 mg) in cocaine-dependent men. The time course of ACTH stimulation paralleled increases in plasma cocaine levels and self-reports of salient drug effects on mood states and did not occur after placebo administration. An opioid mixed agonist-antagonist, buprenorphine (4 mg/day sublingually), suppressed the acute cocaine-induced stimulation of both ACTH and euphoria. Buprenorphine's suppression of postcocaine ACTH and euphoria were not related to differences in plasma cocaine levels or cocaine-induced alterations of cardiovascular function.

Adrenocorticotropic Hormone↗
PubMed1992

Acute effects of cocaine on plasma adrenocorticotropic hormone, luteinizing hormone and prolactin levels in cocaine-dependent men.

Acute cocaine administration alters secretion of anterior pituitary hormones in experimental animals, and cocaine abuse may compromise neuroendocrine function in humans. The goal of this study was to examine cocaine's acute effects on neuroendocrine hormones in cocaine-dependent men. Plasma adrenocorticotropic hormone (ACTH), luteinizing hormone and prolactin levels were measured in 18 men before and after i.v. administration of cocaine (30 mg) or placebo. Each subject served as his own control during the i.v. placebo and cocaine administration conditions. Plasma cocaine levels peaked at 260 ng/ml within 5 min after the i.v. injection. Plasma ACTH levels increased significantly above base-line levels at 5, 15, 30 (P < .01) and 45 min (P < .05) after i.v. cocaine. Plasma luteinizing hormone levels increased significantly above base-line levels at 5 (P < .05) and at 15 min (P < .01) after i.v. cocaine. No changes in plasma ACTH or luteinizing hormone levels were found after i.v. placebo injection. Plasma prolactin levels decreased significantly at 30, 45, 60, 90 and 120 min (P < .01) after both i.v. cocaine and placebo administration. Cocaine-induced increases in plasma ACTH levels may be due to its effects on dopaminergic systems which modulate corticotropin-releasing factor release in brain.

Adrenocorticotropic Hormone↗
PubMed1990

(Pyrimidinyloxy)acetic acids and pyrimidineacetic acids as a novel class of aldose reductase inhibitors.

Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-1-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity.

Acetates↗
PubMed1990

Alcohol effects on hCG-stimulated gonadal hormones in women.

Chronic alcohol abuse is associated with derangements of reproductive function in women. The mechanism of increased risk for alcohol-related abortions and fetal alcohol syndrome is unknown. The goal of this study was to determine if acute alcohol administration affected gonadal steroid hormone levels after administration of human chorionic gonadotropin (hCG) to normal healthy women. hCG was used to simulate the hormonal milieu during the first trimester of pregnancy. Ten women were studied during the mid-luteal phase (between days 17 and 23) of their menstrual cycle. Plasma estradiol, progesterone and prolactin were measured before and after simultaneous administration of 5000 I.U. of hCG (Profasi) and alcohol or placebo solution under double-blind conditions. There was a significant increase in plasma estradiol (P less than .001) and prolactin levels (P less than .01) after hCG and alcohol administration but not after hCG and placebo administration. Plasma progesterone increased significantly (P less than .001) above base line after hCG and placebo administration but this was not observed after hCG and alcohol administration. Since progesterone is essential for the maintenance of pregnancy, alcohol's attenuation of the expected progesterone response to hCG stimulation could increase the risk of spontaneous abortion. An alcohol-induced increase in estradiol after hCG administration could contribute to risk for fetal dysmorphology during the first trimester of pregnancy.

Administration, Oral↗
PubMed1989

Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

Pulse frequency analysis of LH, PRL, testosterone, and cortisol was carried out with the Cluster Analysis Program in eight male cocaine abusers and eight aged-matched normal men. Four of the eight cocaine abusers had hyperprolactinemia (range, 22.08-44.65 micrograms/L). Cocaine users as a group had significantly higher mean peak height (P less than 0.02) than control subjects. Cocaine users with hyperprolactinemia had higher mean peak height than control subjects or cocaine users with normal PRL levels (P less than 0.01). Cocaine users with hyperprolactinemia also had higher mean amplitude increments than control subjects (P less than 0.02). Cocaine users with hyperprolactinemia had a higher mean valley than controls (P less than 0.01) and cocaine users with normal PRL levels (P less than 0.03). However, there were no significant differences in PRL peak frequency, peak duration, or interpulse intervals between cocaine users with or without hyperprolactinemia and control subjects. There were minimal differences between cocaine users and control subjects in pulse frequency analysis of LH parameters; the small differences in mean LH levels and average interpulse interval were not in the abnormal range and were probably not biologically significant. No differences between cocaine users and controls were detected for pulse frequency analysis of testosterone or cortisol. Cocaine-induced hyperprolactinemia may contribute to disorders of sexual and reproductive function in men who abuse the drug, and recent reports that PRL modulates immune function suggest that cocaine-induced derangements of PRL secretion may also contribute to cocaine-related comorbidity in infectious disease. Since cocaine users with hyperprolactinemia had a higher mean valley as well as a higher peak pulse PRL height than control subjects, but did not have greater PRL pulse frequencies, we conclude that hyperprolactinemia in these men may be due to a cocaine-induced derangement of dopaminergic inhibition of basal PRL secretion.

Activity Cycles↗
PubMed1989

Alcohol effects on luteinizing hormone releasing hormone-stimulated anterior pituitary and gonadal hormones in women.

Plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol (E2) and progesterone were measured in 24 normal, adult women before and after i.v. administration of 100 micrograms luteinizing hormone releasing hormone (LHRH; Factrel) and p.o. ingestion of an alcohol (0.694 g of alcohol per kg b.wt.) or placebo solution. Twelve subjects were studied during the early follicular phase of the menstrual cycle and 12 subjects were studied during the midluteal phase of the menstrual cycle. During each menstrual cycle phase, six subjects received placebo solution and six subjects received alcohol solution administered under double-blind conditions. Mean peak blood alcohol levels of 113 to 122 mg/dl were measured 45 to 60 min after initiation of alcohol intake. LHRH stimulated a significant increase in LH after both alcohol (P less than .0001) and placebo (P less than .0001) administration, and this LH increase was equivalent during the follicular and the luteal phases of the menstrual cycle. LHRH also stimulated a significant increase in FSH levels after both alcohol and placebo intake during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in LHRH-stimulated FSH between the alcohol and placebo conditions. Plasma prolactin levels also increased significantly after LHRH administration during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in prolactin response to LHRH administration between the alcohol or placebo conditions during the follicular and luteal phases of the menstrual cycle. Plasma E2 levels did not increase significantly after LHRH administration and placebo alcohol during the follicular phase of the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effects of alcohol on aggressive behavior in squirrel monkeys: influence of testosterone and social context.

Social status and reproductive cycle determine the effects of acute, low doses of alcohol on the social behavior of squirrel monkeys. Alcohol produces biphasic effects on the behavior of dominant but not subordinate monkeys, and only during the mating season. The change in alcohol sensitivity measured in dominant monkeys coincides with changes in plasma testosterone levels. In order to directly study the interaction between alcohol, testosterone and aggressive behavior, testosterone propionate (TP, 25 mg/kg/day, SC) was administered to either dominant or subordinate male monkeys belonging to four separate groups, resulting in significantly elevated plasma levels of testosterone (i.e., 905 +/- 43 ng/ml in subordinates; 171 +/- 19 ng/ml in dominants). Two to three weeks after the beginning of testosterone treatment, the monkeys were administered doses of alcohol (0.1-1.0 g/kg). The behavior of subordinate monkeys was unaffected by TP treatment (even after the dominant monkey from each colony was removed and housed separately for 6 weeks). Testosterone treatment altered the sensitivity of subordinate monkeys to alcohol. Low doses of alcohol increased the frequency of threats, grasps, and displacements exhibited by subordinate monkeys with exogenously elevated testosterone. Daily administration of TP to dominant monkeys during the non-mating season did not affect the behavior of the treated animals in the group, although the body weight of TP-treated monkeys was similar to that measured during the mating season. Low doses of alcohol increased the frequency of threats, grasps, and displacements in dominant monkeys maintained on TP. We also tested the role of social context in maintaining high levels of plasma testosterone, and alcohol sensitivity in dominant monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗