ergoline and amesergide

In 19 patients with major depressive disorder, effective treatment with selective serotonin reuptake inhibitors (SSRIs) or amesergide (AMSG) was associated with increased cerebral perfusion in anterior cingulate cortex (SSRI and AMSG) and in medial prefrontal cortex (AMSG). Both selective serotonin reuptake inhibitors and AMSG exert antidepressant action through the serotonin (5-HT) system as reuptake inhibitors. Amesergide differs from SSRIs in that it is also a highly selective 5-HT antagonist, which may in part account for differences in cerebral blood flow response to treatment.

Topics: Adult; Brain; Brain Mapping; Case-Control Studies; Chi-Square Distribution; Depressive Disorder, Major; Ergolines; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Regional Blood Flow; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon

We hypothesized that the probability of personality disorder ('PROB') predicted by the Temperament and Character Inventory ('TCI') would decline after successful pharmacotherapy of depression.. We administered a computerized version of the TCI to 15 patients with DSM-III-R major depression, before and after treatment with serotonergic antidepressants.. PROB declined from 58.9% +/- 18.0% to 42.4% +/- 22.8% (P < 0.003), due to a significant increase in the Self-Directedness scale. This change in PROB correlated with improvement in self-rated severity of depression (P < 0.02).. TCI prediction of personality disorder is susceptible to state effects of depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Depressive Disorder; Ergolines; Female; Fluoxetine; Fluvoxamine; Humans; Male; Middle Aged; Paroxetine; Personality Disorders; Personality Inventory; Serotonin Antagonists

Prolactin responses to d-fenfluramine (d-FEN) challenge (0.5 mg/kg PO) were examined after pre-treatment with and without the 5-HT2a/2c receptor antagonist amesergide in eight physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with amesergide completely blocked the prolactin (PRL) response to d-FEN challenge in all subjects. These data are consistent with data demonstrating a complete blockade of the PRL response to d-FEN with the 5-HT2a/2c receptor antagonist ritanserin, and suggest that the PRL response to d-FEN challenge in humans may largely be due to activation of the 5-HT2a/2c receptor.

Topics: Adult; Analysis of Variance; Ergolines; Fenfluramine; Humans; Male; Middle Aged; Prolactin; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

Topics: Adult; Antidepressive Agents; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme Inhibitors; Dextromethorphan; Ergolines; Female; Humans; Male; Middle Aged; Mixed Function Oxygenases; Phenotype; Serotonin Antagonists

Amesergide is a selective serotonin 5-HTIC/2 receptor antagonist being developed for the treatment of depression. The potential developmental toxicity of amesergide was evaluated in CD rats and New Zealand white rabbits. Pregnant rats and rabbits were dosed once daily by gavage on Gestation Days 6-17 and 6-18, respectively. Doses for rats were 0, 3, 10, and 30 mg/kg; doses for rabbits and 0, 0.2, 2, and 15 mg/kg. Cesarean sections were performed on rats and rabbits on Gestation Days 20 and 28, respectively. In rats, maternal effects expressed as depression of body weight gain and food consumption were observed at the 30 mg/kg dose level. Fetal viability and morphology were not affected at any dose level. Fetal weight was depressed at the 30 mg/kg dose level. The no-observed-effect level (NOEL) in the rat was 10 mg/kg. In rabbits, maternal effects expressed as a decrease in food consumption occurred at the 2 and 15 mg/kg dose levels; weight gain was depressed at 15 mg/kg. Fetal viability, weight, and morphology were not affected at any dose level. The NOELs for maternal and developmental effects in the rabbit were 0.2 and 15 mg/kg, respectively.

Topics: Abnormalities, Drug-Induced; Animals; Eating; Ergolines; Female; Fetal Viability; Fetus; Intubation, Gastrointestinal; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Teratogens; Uterus; Weight Gain

Amesergide is an orally active ergoline amide, 5-HT2-receptor antagonist with a long duration of action. Since a major metabolite of amesergide is 4-hydroxyamesergide, we questioned whether the formation of this metabolite might contribute to the pharmacological activity and long duration of action observed after oral administration of amesergide. 4-Hydroxyamesergide was a potent 5-HT2-receptor antagonist with an affinity equal to or greater than amesergide under in-vitro conditions as measured by blockade of vascular 5-HT2 receptors, and 5-hydroxytryptamine (5-HT)-amplified ADP-induced rabbit platelet aggregation. Furthermore, 4-hydroxyamesergide, like amesergide, inhibited the pressor response to 5-HT after its intravenous administration to rats and was about 3-fold more potent than amesergide in this regard. 4-Hydroxyamesergide was also a potent inhibitor of vascular 5-HT2 receptors after oral administration to rats. After oral administration, 4-hydroxyamesergide had a similar or slightly greater duration of activity than the parent molecule. 4-Hydroxyamesergide, again like amesergide, also blocked central 5-HT2 receptors after its in-vivo administration to rats as measured by its ability to inhibit quipazine-induced increases in serum corticosterone. Thus, the formation of 4-hydroxyamesergide after oral administration of amesergide to animals and man may contribute to the potency and long duration of action of amesergide as a 5-HT2-receptor antagonist.

Topics: Adenosine Diphosphate; Animals; Blood Pressure; Corticosterone; Ergolines; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Platelet Aggregation; Quipazine; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Cell Surface; Serotonin Antagonists

Previous studies indicated that selected ergolines and tryptamines showed species differences for affinity to the antagonist-labeled 5-HT2 receptor. The present study examined these same compounds for affinity at the agonist-labeled 5-HT2 receptor in rat and squirrel monkey cortical homogenates using [125I]DOI ([125I]1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). As seen with the antagonist-labeled 5-HT2 receptor, N(1) alkyl substitution of either the ergolines or tryptamines resulted in a slight increase or no effect on their affinity for the agonist-labeled rat 5-HT2 receptor. In contrast, these same N(1) substitutions resulted in significant decreases in affinity for the agonist-labeled monkey 5-HT2 receptor. It was also noted that N(1)-unsubstituted ergolines and tryptamines (such as ergonovine, LY86057, LY193525 and 5-methoxytryptamine) tended to have higher affinity for the monkey versus the rat agonist-labeled receptor. However, the N(1) alkyl-substituted ergolines and tryptamines (such as mesulergine, LY53857, amesergide, N(1)-isopropyltryptamine and N(1)-isopropyl-5-methoxytryptamine) showed significantly lower affinity for the monkey versus the rat 5-HT2 receptor. These data suggest that, at least in relation to the N(1) position, ergolines and tryptamines bind in a similar orientation. These results are also discussed in terms of what amino acid differences between species may account for this structure-activity relationship.

Topics: Amphetamines; Animals; Cerebral Cortex; Ergolines; Ergonovine; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Saimiri; Serotonin Antagonists; Serotonin Receptor Agonists; Species Specificity; Structure-Activity Relationship; Tryptamines

A series of tricyclic (nor-D) partial ergolines were synthesized via a highly convergent enantiospecific strategy, ultimately arising from a racemic tricyclic ketone. Michael addition to an acrylamide, followed by reductive methylation, afforded the key intermediate. Selective deprotection and oxidation provided the tricyclic ergoline. Vascular 5HT2 receptor interactions for the partial ergolines were dramatically reduced compared to the parent ergoline, amesergide, as determined in vivo by activation of a pressor response or blockade of 5HT-induced pressor responses in pithed rats. The desisopropyl tricyclic ergolines possessed some modest pressor activity that was unlikely to be related to 5HT2 receptor activation since these compounds did not inhibit the pressor response to serotonin. In contrast, the isopropyl tricyclic ergolines exhibited no agonist activity, but inhibited the pressor response to serotonin at 1 mg/kg i.v. The ergoline amesergide inhibited the pressor response to serotonin in doses of 0.01-0.1 mg/kg i.v. The homochiral isopropyl tricyclic ergoline was more potent as a 5HT2 receptor antagonist than the epimeric (unnatural stereochemistry) analogue. Thus, the isopropyl moiety on the indole nitrogen is important for vascular 5HT2 receptor affinity in the rat. Most importantly, these data suggest that conformational rigidity of the ergoline D-ring is required for optimal 5HT2 receptor interactions in the rat.

Topics: Animals; Blood Pressure; Ergolines; Molecular Structure; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Structure-Activity Relationship

8B-N-cyclohexyl-6-methyl-1(1-methylethyl)ergoline-8-carboxamide (LY237733) is an ergoline with potent and highly selective 5-hydroxytryptamine (5-HT) antagonist activity. The in vitro radioligand displacement studies showed that LY237733 has a preferential affinity for 5-HT1c and 5-HT2 receptors compared to other monoaminergic receptors. This characteristic is shared with other previously described ergoline 5-HT antagonists, such as LY53857 and sergolexole. In parallel ligand displacement assays, LY237733 had a similar potency to sergolexole. LY237733 was equipotent to sergolexole, but slightly less potent than LY53857 in the antagonism of 5-HT-induced elevation in blood pressure and quipazine-induced elevation in corticosterone levels, which are considered to be measures of 5-HT2 and possibly 5-HT1c antagonist activity. LY237733 failed to antagonize pergolide or 8-hydroxy-2-(di-n-propylamino)tetralin-induced elevations in serum corticosterone levels, indicating selectivity for the 5-HT1c/2 receptor, relative to 5-HT1a and D2 dopaminergic receptors. The only in vivo response that could be detected after administration of LY237733 alone in doses less than 1 mg/kg was the amplification of male rat sexual behavior. LY237733 was 10 to 100 times more potent than LY53857 or sergolexole in augmenting sexual responses of male rats with different levels of sexual response capacity. LY237733 has a much longer serum half-life than sergolexole. These studies have provided the pre-clinical rationale to evaluate the effects of this compound in the treatment of sexual disorders such as psychogenic erectile dysfunction, and other therapeutic indications for a 5-HT2 antagonist, including depression, anxiety, schizophrenia and migraine.

Topics: Animals; Behavior, Animal; Brain; Cardiovascular System; Cattle; Copulation; Corticosterone; Drug Evaluation, Preclinical; Ergolines; Female; Male; Membranes; Radioligand Assay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Serotonin Antagonists; Swine

Human platelets are known to possess 5HT2 receptors which, when activated, amplify the aggregation response produced by other aggregating agents. Several 5HT2 receptor antagonists, including ketanserin and ritanserin, are known to antagonize serotonin-mediated aggregation of human platelets. In the present study, we document the ability of three ergoline 5HT2 receptor antagonists, LY53857, sergolexole, and LY237733, to antagonize the serotonergic component of the human platelet aggregation response. Potencies of the ergoline esters (LY53857 and sergolexole) and the ergoline amide (LY237733) to inhibit serotonin-amplified platelet aggregation responses were similar to the potencies of ketanserin and ritanserin under the conditions of our study. Furthermore, all five 5HT2 receptor antagonists were capable of fully inhibiting the serotonergic component of the platelet aggregation response. In contrast to these potent ergoline esters and amides, 1-isopropyl dihydrolysergic acid (up to 10(-5)M), a putative metabolite of the ergoline esters, was ineffective under these in vitro conditions. These data are consistent with the high potency of these ergolines as antagonists of 5HT2 receptors and further support the involvement of 5HT2 receptors on human platelets in the amplifying response to serotonin.

Topics: Adult; Ergolines; Female; Humans; Ketanserin; Lysergic Acid; Male; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists