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An efficient and direct route to ergot alkaloid (-)-chanoclavine I (3) is described using the inexpensive compound (2R)-(+)-phenyloxirane (15) as a chiral pool in 13 steps with 17% overall yield. Key features of the synthesis include a palladium-catalyzed intramolecular aminoalkynylation of terminal olefin and a rhodium-catalyzed intramolecular [3 + 2] annulation. An oxygen-substituted ergoline derivative (-)-25 was also achieved by using the same strategy.

Objective To determine the efficacy and reliability of cabergoline and pregnant mare's serum gonadotrophin (PMSG) for induction of oestrus in bitches with primary or secondary anoestrus. Procedures We studied 39 healthy bitches of various breeds aged 2-6 years and in primary or secondary anoestrus: 20 bitches were administered 5 mg/kg/day cabergoline orally until day 2 after the onset of pro-oestrus or for a maximum of 42 days, and 19 bitches were administered 20 IU/kg/day PMSG intramuscularly for 5 consecutive days, followed by an additional single injection of 25 IU/kg of human chorionic gonadotrophin on the fifth day. Results The rates of oestrus induction in the primary and secondary anoestrous bitches treated with cabergoline and PMSG were found to be similar. Pregnancy and whelping rates in the cabergoline group were statistically different from the rates in the PMSG group (P < 0.001). Conclusion Cabergoline is more effective and reliable for the induction of a fertile oestrus in bitches with primary or secondary anoestrous.

The structure of the ergoline derivative 1,1-Diethyl-3-[(2R,3R,5R,8S,10S)-2,3-dihydro-2,6-dimethyl-8-ergolinyl]-urea has been determined by X-ray single crystal diffraction at three temperatures: 295, 50 and 15 K. Large displacement parameters of the diethyl-urea side group atoms cause rather improper bond distances at room temperature which, after cooling, adopt normal values. An inspection of the displacement parameters expressed in U eq's, shows that even the temperature reduction from 50 to 15 K causes an average decrease of U eq's by 33%. At room temperature, the individual displacement parameters depend strongly on the atomic distances from the molecular center of gravity. This dependence disappears almost completely at 15 K.

This is the first report of successful induction of normal estrus and ovulation in breeder bitches with as a low dose as 0.6 mu g/kg/day of cabergoline formulation marketed for use in women. Sixty-one pure breed bitches from various breeds were used in the study at their already determined periods of anestrus. Twenty-four dogs formed the control group, while 37 bitches were administered with two different doses of cabergoline (recommended dose group, n = 10, 5 mu g/kg/day and low dose group, n = 27, 0.6 mu g/kg/day). Induced estrus rates and mean treatment and proestrus durations of dogs in these two dose groups were compared. At the second phase of the study, the effects of 500 IU human chorionic gonadotropin (hCG) administered on days 1 and 3 of estrus induced by the low dose of cabergoline, on the duration of behavioral estrus, ovulation rates, pregnancy rates and the number of offspring were investigated. For this purpose, the dogs with signs of proestrus (22/27) following the treatment in the low dose group were assigned into two subgroups. Five hundred IU of hCG (Pregnyl, Organon, Turkey) was intramuscularly administered to eight of these dogs [low dose (hCG+) group] on days 1between days 8-45 and 4-48 (mean: 23.63 +/- 14.33 and 24.41 +/- 14.31 days), in the ratio of 80.0 and 81.5%, respectively (p > 0.05). In both dose groups, post-treatment interestrous intervals were significantly shorter than both those of the control group and their own pre-treatment interestrous intervals (p < 0.05). Ovulation rates, pregnancy rates and mean number of offspring delivered by the dogs in the recommended dose, low dose (hCG-), low dose (hCG+) and control groups were found to be similar (p > 0.05). However, the mean duration of behavioral estrus of the dogs in the low dose (hCG+) group was found to be significantly longer compared to dogs in all other groups (p < 0.05). In both dose groups, no correlation could be found between the anestrus stages and treatment durations (p > 0.05). Shortly, it has been concluded from the study that (1) normal and fertile estrus can be induced more economically in bitches during different stages of anestrus using as a low dose of 0.6 mu g/kg of cabergoline formulation marketed for use in women, and that (2) hCG injections on days 1 and 3 of the estrus induced by this method has no positive effects on the ovulation rates, pregnancy rates and the number of offspring per pregnancy. (C) 2006 Elsevier B.V. All rights reserved. and 3 of estrus. The remaining 14 dogs were not treated with hCG [low dose (hCG-) group]. An aqueous solution of cabergoline (Dostinex, Pharmacia, Italy) was orally administered until 2 day after the onset of proestrus or for a maximum of 42 days. Blood samples were taken daily from all treatment and 11 control bitches during the first five days of behavioral estrus to measure progesterone concentrations. In the recommended dose and low dose groups, estrus was induced.

Twelve hyperprolactinemic women were administered the α aminoergoline derivative, CU 32-085 (Sandoz, Inc., East Hanover, NJ), in order to determine its effect on prolactin (PRL) secretion. The mean pretreatment serum PRL level was 145.0 ± 11.5 ng/ml. Significant declines of serum PRL occurred with total daily doses of CU 32-085 of 0.1 to 0.5 mg ( P

The behavioral effects of IP administration of lisuride, a non-hallucinogenic iso-lysergic acid amide analog structurally related to d-lysergic acid diethylamide (LSD), were examined in 15 cats. Ten animals were given saline or 6.25, 12.5, 25, 50, or 100 micrograms/kg of lisuride and observed for 1 h by a rater blind to dose. There was a statistically significant effect of lisuride dose on the frequency of occurrence of the behaviors limb flicking, grooming, and abortive grooming. A time-course study with five cats at the most effective lisuride dose, 50 micrograms/kg, revealed that the frequencies of occurrence of these behaviors reached a maximum during the first 2 h post dose, and were comparable to frequencies after saline by 6 h post dose. An acute tolerance study with four cats scored for 90 min post dose revealed no significant tolerance to a 50 micrograms/kg lisuride test dose administered 6, 24, or 72 h after an initial 50 micrograms/kg dose. Acute cross tolerance studies with four cats scored for 90 min after an initial dose of 50 micrograms/kg of LSD or of lisuride, followed 24 h later by 50 micrograms/kg of lisuride or LSD, revealed no significant cross tolerance. The potency of lisuride relative to LSD was evaluated in six cats that were scored for 60 min following 25 and 50 micrograms/kg of LSD and of lisuride. On a molar basis, scores after lisuride were 51% and 67% those after LSD for limb flicking and grooming. These results indicate that lisuride, a non-hallucinogenic iso-lysergic acid derivative, is a false positive in the animal behavior model for hallucinogens.

Compound 83636 (lergotrile), an ergoline derivative, inhibits prolactin release in vitro and in vivo in animals. Studies were designed to evaluate its clinical pharmacologic effects in man. Its chronic administration (2 mg 3 times daily) to normal volunteers and patients results in a decrease in serum prolactin levels. Pretreatment of subjects with single doses of 2, 4, or 6 mg of Compound 83636 delayed the onset of perphenazine-induced elevation of serum prolactin in a dose-dependent fashion. Administration of Compound 83636 (4 or 6 mg) 1 hr after perphenazine administration resulted in a decrease in the elevated serum prolactin levels towards baseline within 15 to 30 min. One week's chronic treatment with Compound 83636 (2 mg 3 times daily) attenuated the expected perphenazineinduced rise in serum prolactin. Compound 83636 appeared to have no significant effect on growth hormone, T3, T4, LH or FSH when compared to determinations made during a placebo control period. It appears that Compound 836...

The ergoline derivative metergoline was administered at the daily dose of 12mg for 1 to 28 months to 41 hyperprolactinemic women (20 with a normal sella turcica according to tomography, 16 with radiologic evidence of pituitary microadenoma, and 5 with macroadenoma). Serum prolactin (PRL) concentration was reduced by treatment to below 50% of pretreatment values in 29 patients, with actual normalization (serum PRL

Substitution of the ergoline derivative terguride 1 in the positions 2, 12 and 13 is effected by reaction of the respective bromo-ergolines with tert .-butyllithium and an electrophile in a regioselective manner.

The clinical efficacy of CU 32-085, a novel ergoline derivative, in puerperal lactation inhibition was investigated in 41 healthy postpartum women and compared with serum concentrations of prolaction (PRL) and CU 32-085. The women received 0.5 mg CU 32-085 twice daily for 14 days. In 40 women (i.e. 97%) treatment with CU 32-085 successfully inhibited lactation; slight to moderate breast activity appearing during the first few days receded spontaneously. 1 woman experienced full milk let-down on day 5 of treatment. No rebound lactational phenomena were recorded. 5 h after the initial dose, mean serum PRL concentrations decreased by 82% (from 169 to 30 ng/ml), and PRL values remained at that level during the course of treatment. The mean serum concentrations of CU 32-085 showed an inverse pattern compared to PRL. CU 32-085 was well tolerated, with transient slight to moderate dizziness, headache and nausea reported by 12 women (29%) following the initial dose. These disappeared after an average of 3 h. Routine safety chemistries remained within the normal range, and no statistically significant differences between the treatment group and the control group (25 normal nursing postpartum women) were encountered. It is concluded that CU 32-085, a potent dopamine agonist, is an effective and well-tolerated treatment in the indication of postpartum lactation inhibition.

The effect of the new, prolactin-lowering ergoline derivative FCE21336 and medroxyprogesterone acetate (MPA) given alone and in combination was tested on DMBA-induced mammary tumors in rats. FCE 21336 (0.05 and 0.4 mg/kg p.o.) and MPA (25 and 50 mg/kg s.c.), administered 5 days/week for 4 weeks, inhibited the growth of established tumors and reduced serum prolactin levels. Combined treatment inhibited tumor growth more than single treatment. These results were confirmed in a second experiment: the antitumor effect of the combination of FCE 21336 (0.1 mg/kg p.o.) and MPA (50 mg/kg s.c.) was greater than that of the single treatment and was similar to the effect of ovariectomy. In this experiment rats with tumors that did not respond to 4 weeks' treatment with FCE 21336 (0.1 mg/kg p.o.) were treated during the next 4 weeks with MPA (50 mg/kg s.c.). MPA was effective on FCE 21336-unresponsive tumors. These data indicate that combined FCE 21336 and MPA treatment is more effective than single treatment and that MPA is effective on tumors not sensitive to the prolactin-lowering drug.

LY141865 (LY), an ergoline derivative, was investigated for ocular effects in rabbits and monkeys. LY lowered intraocular pressure (IOP) bilaterally in monkeys and rabbits, prevented the bilateral rise in IOP caused by oral waterloading in rabbits and slowed the rate of IOP recovery bilaterally in rabbits. The ocular hypotensive activity of LY in rabbits was inhibited by sympathectomy and pretreatment with sulpiride. Since LY has cardiovascular effects that are centrally mediated, ocular responses may also be mediated, in part, by an action in the CNS.

The ergoline derivative, Metergoline, in a dosage of 4 to 24 mg/day, was administered for one to eight months to 42 patients with hyperprolactinemic amenorrhea. Mean serum prolactin (PRL) concentrations before treatment were 91.2 ng/mL in the patients with functional hyperprolactinemia (N = 29) and 256.9 ng/mL in the patients with pituitary tumor (N = 13). Within four weeks, Metergoline treatment reduced these PRL concentrations to 39.5 ng/mL and 82.9 ng/mL, respectively. In this study Metergoline treatment resulted in restoration of menstruation in a total of 37 patients; 28 patients ovulated, and eight became pregnant. It is considerably more effective in functional hyperprolactinemia than in hyperprolactinemia caused by adenoma.

Sermion (nicergoline) is an ergoline derivative clinically active in chronic cerebral vascular insufficiency [1] and in patients with senile dementia [2].

Mit Hilfe vond-6-Methyl-8-ergolin-I-ylacetamid-Tartarat, VUFB-6683 wurde bei saugenden Ratten das Gewicht und der Prolaktinspiegel der Adenohypophyse herabgesetzt und die Laktation gehemmt.