ergoline and lysergol

The current review emphasizes on the herbal bioenhancers which themselves do not possess inherent pharmacological activity of their own but when co-administered with Active Pharmaceutical Ingredients (API), enhances their bioavailability and efficacy. Herbal bioenhancers play a crucial role in enhancing the bioavailability and bioefficacy of different classes of drugs, such as antihypertensives, anticancer, antiviral, antitubercular and antifungal drugs at low doses. This paper highlights various natural compounds that can be utilized as an efficient bioenhancer. Several herbal compounds including piperine, quercetin, genistein, naringin, sinomenine, curcumin, and glycyrrhizin have demonstrated capability to improve the pharmacokinetic parameters of several potent API. This article also focuses on various United States patents on herbal bioenhancers, which has proved to be beneficial in improving oral absorption of nutraceuticals like vitamins, minerals, amino acids and certain herbal compounds. The present paper also describes proposed mechanism of action, which mainly includes absorption process, drug metabolism, and action on drug target. The herbal bioenhancers are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Inspite of the fact that herbal bioenhancers provide an innovative concept for enhancing the bioavailability of several potent drugs, there are numerous bioenhancers of herbal origin that are yet to be explored in several vital areas. These bioenhancers must also be implied to enhance the bioavailability and bioefficacy through routes other than the oral route of drug delivery. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response.

Topics: Adjuvants, Pharmaceutic; Alkaloids; Benzodioxoles; Biological Availability; Carum; Cuminum; Curcumin; Ergolines; Flavanones; Genistein; Glycyrrhizic Acid; Humans; Morphinans; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Quercetin; Zingiber officinale

The enantioselective synthesis of (+)-isolysergol was completed in 18 steps, and an overall yield of 11% was obtained from (2

Topics: Catalysis; Cyclization; Ergolines; Molecular Structure

Key transformations in a four-step synthesis of the

Topics: Alkenes; Dopamine Agonists; Ergolines; Ergot Alkaloids; Esters; Hydrogen; Serotonin

A catalytic enantioselective construction of vicinal stereocenters is reported. The reaction takes advantage of thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester to afford exceptional levels of enantioselectivity (up to 97 % ee) with moderate diastereoselectivity (up to 4:1). Using this method, a cross-conjugated ester was synthesized in few steps, from which a 6-endo-trig cyclisation led to the formation of all required functionalities for total syntheses of ergot alkaloids. The strategy not only offers first total syntheses of ergot alkaloids, festuclavine (1 c), and pyroclavine (1 e), and but also an efficient and general approach to other congeners such as, lysergol (1 b), and isolysergol (1 d).

Topics: Catalysis; Cyclization; Ergolines; Ergot Alkaloids; Nitroso Compounds; Proline; Stereoisomerism

An efficient synthesis of ergot alkaloid lysergol and its analogues is described, providing compounds for functional evaluation at the human 5-HT

Topics: Ergolines; Molecular Structure; Receptors, Serotonin

Nowadays psychoactive plants marketed as "legal highs" or "herbal highs" increase in popularity. One popular "legal high" are the seeds of the Hawaiian baby woodrose Argyreia nervosa (Synonym: Argyreia speciosa, Convolvolus speciosus). At present there exists no study on A. nervosa seeds or products, which are used by consumers. The quality of commercial available A. nervosa seeds or products is completely unknown. In the present study, a commercial available seed collection (five seeds labeled "flash of inspiration", FOI) was analyzed for ergot alkaloids together with an A. nervosa product (two preparations in capsule form, "druids fantasy", DF). For this purpose high performance liquid chromatography high resolution tandem mass spectrometry (HPLC-HRMS/MS) technique was employed. Besides the major ingredients such as lysergic acid amide (LSA) and ergometrine the well known A. nervosa compounds lysergol/elymoclavine/setoclavine, chanoclavine and the respective stereoisomers were detected in DF, while only LSA and ergometrine could be found in FOI. In addition, in DF lysergic acid was found, which has not been reported yet as ingredient of A. nervosa. In both products, DF as well as in FOI, LSA/LSA-isomers were dominant with 83-84% followed by ergometrine/ergometrinine with 10-17%. Therefore, LSA, followed by ergometrine/ergometrinine, could be confirmed to be the main ergot alkaloids present in A. nervosa seeds/products whereas the other ergot alkaloids seemed to be of minor importance (less than 6.1% in DF). The total ergot alkaloid amounts varied considerably between DF and FOI by a factor of 8.6 as well as the LSA concentration ranging from 3 μg (lowest amount in one FOI seed) to approximately 34 μg (highest amount in one DF capsule). Among the FOI seeds, the LSA concentration varied from approximately 3-15 μg per seed. Thus, the quality/potency of seeds/preparations depends on the amount of ergot alkaloids and the intensity of an expected trip is totally unpredictable.

Topics: Alkaloids; Chromatography, Liquid; Convolvulus; Ergolines; Ergonovine; Humans; Indoles; Lysergic Acid Diethylamide; Molecular Structure; Psychotropic Drugs; Seeds; Tandem Mass Spectrometry

Antibacterial activity of lysergol (1) and its semi-synthetic derivatives (2-14) and their synergy with the conventional antibiotic nalidixic acid (NA) against nalidixic acid-sensitive (NASEC) and nalidixic acid-resistant (NAREC) strains of Escherichia coli were evaluated. Lysergol (1) and derivatives (2-14) did not possess antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration (MIC) of NA. All the derivatives showed two- to eightfold reduction in the MIC of NA against NAREC and NASEC. Further, lysergol (1) and its derivatives 10 and 11 brought down eightfold reductions in the MIC of tetracycline (TET) against multidrug-resistant clinical isolate of E. coli (MDREC). Treatment of these strains with the combinations of antibiotics and lysergol and its derivatives 10 and 11 (at reduced concentrations) significantly decreased the viability of cells. In an another observation, lysergol and its derivatives 10 and 11 inhibited ATP-dependent efflux pumps, which was evident by ATPase inhibition and down-regulation of multidrug ABC transporter ATP-binding protein (yojI) gene. These results may be of great help in antibacterial drug development from a very common, inexpensive, and non-toxic natural product.

Topics: Adenosine Triphosphatases; Anti-Bacterial Agents; Anti-Infective Agents; ATP-Binding Cassette Transporters; Drug Resistance, Bacterial; Drug Synergism; Ergolines; Ergot Alkaloids; Escherichia coli; Escherichia coli Proteins; Microbial Sensitivity Tests; Nalidixic Acid; Tetracycline

A rapid, simple, sensitive, gradient and reproducible, reverse-phase high-performance liquid chromatographic method was developed for the quantitative estimation of bioactive alkaloids, lysergol and chanoclavine in the seeds of Ipomoea muricata. The clavine alkaloid, lysergol, is a bioenhancer for the drugs and nutrients. The samples were analyzed by reverse-phase chromatography on a Waters spherisorb ODS2 column (250 × 4.6 mm, i.d., 10 µm) using binary gradient elution with acetonitrile and 0.01 m phosphate buffer (NaH₂PO₄) containing 0.1% glacial acetic acid at a flow rate of 0.8 mL/min, a column temperature of 25 °C and UV detection at λ 254 nm. The limits of detection (LOD) and quantitation (LOQ) were 0.035 and 0.106 µg/mL for lysergol and 0.039 and 0.118 µg/mL for chanoclavine, respectively. Standard curves were linear in the range of 2-10 µg/mL (r > 99) for both analytes. Good results were achieved with respect to repeatability (RSD < 2%) and recovery (99.20-102.0). The method was validated for linearity, accuracy repeatability, LOQ and LOD. The method is simple, accurate and precise, and may be recommended for routine quality control analysis of I. muricata seed extracts containing these two clavine alkaloids (1, 2) as bioactive principles of the herb.

Topics: Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Ergolines; Ipomoea; Least-Squares Analysis; Reproducibility of Results; Seeds; Sensitivity and Specificity

A sensitive and simple HPLC method was developed for the simultaneous quantification of berberine and lysergol in rat plasma. The chromatographic separation was achieved on a C(18) column using isocratic elution with methanol-acetonitrile-0.1% ortho-phosphoric acid (25:20:55, v/v/v), pH adjusted to 6.5 with triethylamine and detected at a UV wavelength of 230 nm. The extraction of the berberine and lysergol from the rat plasma with methylene chloride resulted in their high recoveries (82.62 and 90.17%). HPLC calibration curves for both berberine and lysergol based on the extracts from the rat plasma were linear over a broad concentration range of 50-1000 ng/mL. The limit of quantification was 50 ng/mL. Intra- and inter-day precisions were <15% and accuracy was 87.12-92.55% for berberine and 87.01-92.26% for lysergol. Stability studies showed that berberine and lysergol were stable in rat plasma for short- and long-term period for sample preparation and analysis. The described method was successfully applied to study the pharmacokinetics of berberine as well as lysergol following oral administration in Sprague-Dawley rats. The results of the study inferred that lysergol improved the oral bioavailability of berberine.

Topics: Administration, Oral; Analysis of Variance; Animals; Berberine; Biological Availability; Chromatography, High Pressure Liquid; Drug Stability; Drug Synergism; Ergolines; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Stimulation of the sympathetic nerve in the thoracic cavity often does not inhibit, but increases stomach contractions in dogs. Blockade of α- and β-adrenoceptors potentiates this stimulatory effect, while blockade of S(1,2)-receptors localized mainly in smooth muscle cells eliminates it. It is concluded that sympathetic nerve includes serotonergic fibers stimulating gastric motility.

Topics: Adrenergic Antagonists; Adrenergic Fibers; Animals; Dogs; Electric Stimulation; Ergolines; Gastrointestinal Motility; Phentolamine; Propranolol; Serotonergic Neurons

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.

Topics: Catalysis; Cyclization; Ergolines; Ergot Alkaloids; Indoles; Lysergic Acid; Magnetic Resonance Spectroscopy; Molecular Structure; Palladium; Stereoisomerism

To determine the effects of feeding ryegrass seed containing ergovaline to sheep selected for resistance or susceptibility to ryegrass staggers on concentration of lysergol (a metabolite of ergovaline) in urine, prolactin in plasma, rectal temperature and respiration rate.. Two experiments were carried out using 12 Romney crossbred ewe lambs aged 9 months, comprising animals resistant (n=4), susceptible (n=4) or outcross (n=4) to ryegrass staggers. In Experiment 1, sheep were given either a single (Part A) or six (Part B) feed (s) of endophyte-infected seed containing ergovaline at 30 mg/kg dry matter (DM), at 42 μg ergovaline/kg bodyweight (BW), to simulate acute and chronic exposure to ergovaline, respectively. The concentration and excretion of lysergol in urine and concentration of prolactin in plasma were measured over 3 and 12 days, for Parts A and B respectively. In Experiment 2, after a recovery period of 7 days, the same sheep were fed with ergovaline at 67 μg/kg of BW for 7 days. Soon after the seventh feed the sheep were moved to a hothouse at 36.5°C and 60% humidity, and 3 h later their rectal temperatures and respiration rates were measured.. The concentration of lysergol and excretion in urine increased to a peak between 6 and 9 h after exposure to ergovaline whereas the concentration of prolactin in plasma was markedly reduced. Differences in concentration and rate of excretion of lysergol in urine between animals resistant, outcross and susceptible to ryegrass staggers were not significant (p>0.1). The animals resistant to ryegrass staggers had a lower rectal temperature (p<0.05) and a faster respiration rate than the outcross and susceptible groups when exposed to high ambient temperature and high humidity.. This study showed that excretion of lysergol in urine increased with each exposure of sheep to ergovaline. Animals genetically resistant to ryegrass staggers exhibited a lower rectal temperature and a faster respiration rate than those susceptible, demonstrating the possible cross resistance of sheep to ergovaline in a population originally selected for resistance to ryegrass staggers. Hence potential exists to select animals resistant to ryegrass staggers that are also resistant to ergovaline.

Topics: Analysis of Variance; Animal Feed; Animals; Body Temperature; Ergolines; Ergotamines; Lolium; Mycotoxicosis; Mycotoxins; Plants, Toxic; Prolactin; Respiratory Rate; Sheep

The first enantioselective synthesis of (+)-isolysergol was completed in 12 steps from commercially available materials by a novel approach that features a late stage microwave-mediated, diastereomeric ring-closing metathesis catalyzed by a chiral molybdenum catalyst to simultaneously form the D ring and set the stereocenter at C(8).

Topics: Catalysis; Cyclization; Ergolines; Microwaves; Molecular Structure; Molybdenum; Stereoisomerism

Ergot alkaloids and their synthetic analogs have been reported to exhibit broad biological activity. We investigated direct construction of the C/D ring system of ergot alkaloids based on palladium-catalyzed domino cyclization of amino allenes. With this biscyclization as the key step, total synthesis of (+/-)-lysergic acid, (+/-)-lysergol, and (+/-)-isolysergol was achieved.

Topics: Alkadienes; Bromine; Catalysis; Cyclization; Ergolines; Indoles; Lysergic Acid; Palladium; Stereoisomerism

Ergot alkaloids present in endophyte-infected tall fescue induce fescue toxicosis in livestock consuming the plant. The lysergic acid (LA) ring structure is a common moiety among the ergot alkaloids. Little is known about the bioavailability of LA because of limitations in available analytical protocols. Thus, a high-performance liquid chromatography procedure was developed to analyze biological matrices for LA. The biological matrices of interest were tall fescue straw and seed, and ruminant feces, urine, and ruminal fluid. Lysergic acid was added to each matrix at a high (150 ng/ml) or low (30 ng/ml) level. Using the high-level addition, the greatest recovery of LA was obtained from ruminal fluid, feces, and urine (P < 0.05), with an average 85.1% recovered. At the low level, a greater recovery of added LA was observed in the ruminal fluid, urine, and feces (82.1%; P < 0.05) than that in the other 2 matrices (62.6%). The limit of quantitation (LOQ) in ruminal fluid and urine was 5.5 and 18.4 ng/ml, respectively. Seed, straw, and feces had higher LOQ (24.2, 14.5, and 36.0 ng/g, respectively). Limit of detection (LOD) was 1.64, 10.80, 4.35, 5.52, and 7.26 ng/g for ruminal fluid, feces, urine, seed, and straw, respectively. To test the assay in vivo, samples of ruminal fluid and urine were collected from steers consuming a diet containing 400 ng of ergovaline/g and 30 ng of LA/g. All matrices sampled resulted in levels above the LOD and LOQ for the assay, indicating that this assay is sufficiently sensitive for use in assessing the bioavailability of LA.

Topics: Animals; Cattle; Chromatography, High Pressure Liquid; Ergolines; Ergotamines; Lysergic Acid; Male; Molecular Structure; Poaceae; Rumen

Tall fescue toxicosis and other maladies in livestock result from the ingestion of vasoconstrictive ergot alkaloids produced by fungal endophytes associated symbiotically with the grass. In order to facilitate future analyses of grass extracts considered responsible for outbreak of related livestock diseases, we examined the electrospray ionization mass spectra of specific ergot alkaloids under conditions that permit protonation. Our purposes were both to record the spectra with interpretation of mechanisms of fragmentation and to derive commonalities that would allow the prediction of mass spectra of related compounds for which standards were not readily available. With [M + H](+) values in parentheses, water-insoluble lysergic acid peptide ergot derivatives ergovaline (m/z 534), ergotamine (m/z 582), ergocornine (m/z 562), ergocryptine (m/z 576) and ergocrystine (m/z 610) exhibited a consistent loss of water (-18 u) from the C-12' alpha-hydroxy functionality. Of this group, ergovaline and ergotamine generated an m/z 320 fragment deriving from cleavage of ring E amide and ether functions with retention of the peptide ring system methyl group. Ergocornine, ergocryptine and ergocrystine similarly formed an m/z 348 fragment with retention of isopropyl. These assignments were supported by the lack of similar fragments from the water-soluble ergot ergonovine, which lacks a peptide ring system. Clavine-type ergot alkaloids lysergic acid and lysergol lack any substituents beyond simple ones directly on the C-8 position and, similarly to ergonovine, lack significant fragments at m/z 268, 251 and 225 shared by the peptide ergot alkaloids.

Topics: Animal Feed; Animals; Ergolines; Ergonovine; Ergot Alkaloids; Ergotamine; Ergotamines; Festuca; Food Contamination; Horse Diseases; Horses; Lysergic Acid; Spectrometry, Mass, Electrospray Ionization

Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected tall fescue. It is generally accepted that ergovaline is the toxic component of endophyte-infected tall fescue, but there is no direct evidence to support this hypothesis. The objective of this study was to examine relative and potential transport of ergoline and ergopeptine alkaloids across isolated gastric tissues in vitro. Sheep ruminal and omasal tissues were surgically removed and placed in parabiotic chambers. Equimolar concentrations of lysergic acid, lysergol, ergonovine, ergotamine, and ergocryptine were added to a Kreb's Ringer phosphate (KRP) solution on the mucosal side of the tissue. Tissue was incubated in near-physiological conditions for 240 min. Samples were taken from KRP on the serosal side of the chambers at times 0, 30, 60, 120, 180, and 240 min and analyzed for ergot alkaloids by competitive ELISA. The serosal KRP remaining after incubation was freeze-dried and the alkaloid species quantified by HPLC. The area of ruminal and omasal tissues was measured and the potential transportable alkaloids calculated by multiplying the moles of transported alkaloids per square centimeter of each tissue type by the surface area of the tissue. Studies were conducted to compare alkaloid transport in reticular, ruminal, and omasal tissues and to determine whether transport was active or passive. Ruminal tissue had greater ergot alkaloid transport potential than omasal tissue (85 vs 60 mmol) because of a larger surface area. The ruminal posterior dorsal sac had the greatest potential for alkaloid transport, but the other ruminal tissues were not different from one another. Alkaloid transport was less among reticular tissues than among ruminal tissues. Transport of alkaloids seemed to be an active process. The alkaloids with greatest transport potential were lysergic acid and lysergol. Ergopeptine alkaloids tended to pass across omasal tissues in greater quantities than across ruminal tissues, but their transport was minimal compared to lysergic acid and lysergol.

Topics: Animals; Biological Transport; Ergolines; Ergonovine; Ergot Alkaloids; Ergotamine; Female; Intestinal Absorption; Linear Models; Lysergic Acid; Omasum; Random Allocation; Reticulum; Rumen; Sheep; Sodium Azide

Three series of cycloalkanecarboxylic esters derived from the naturally occurring clavine alkaloids lysergol, dihydrolysergol-I, and elymoclavine were synthesized to study their interaction with 5-HT2A receptors and alpha1-adrenoceptors in rat tail artery and aorta, respectively. Especially cycloalkanecarboxylic esters derived from lysergol showed complex behavior as partial agonists and antagonists of the contractile effect of 5-HT. Within this group, partial 5-HT2A receptor agonist activity was most potent for cyclopropanecarboxylic ester 6a (pKP = 7.67, alpha = 0.21) and decreased as the volume requirement of the alicyclic ring increased. This tendency was echoed in experiments where the compounds were used as antagonists of the contractile effect of 5-HT. From the structure-activity study, the N-1-isopropyl homologue of 6a, compound 6b, emerged as the ligand with the highest affinity for rat 5-HT2A receptors (pA2 = 8.74). For cycloalkanecarboxylic esters derived from dihydrolysergol-I and elymoclavine, no clear structure-affinity relationship could be deduced, although those compounds that had smaller cycloalkyl rings in the acyl portion and an isopropyl substituent at N-1 showed the highest 5-HT2A receptor affinity. On the other hand, cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine displayed low or marginal affinity at alpha1-adrenoceptors. A further aim of the study was to examine to what extent the complete removal of the acyl portion of the esters would affect 5-HT2A receptor affinity. The parent alcohols of the three series of N-1-isopropyl homologues, 1-isopropyllysergol (1b), 1-isopropyldihydrolysergol-I (2b), and 1-isopropylelymoclavine (3b), displayed higher affinity for 5-HT2A receptors (pA2 = 9.15, 8.50, 9.14) than the corresponding esters. Compounds 1b-3b had no contractile effects by themselves and displayed low affinity at guinea-pig 5-HT1B receptors and rat alpha1-adrenoceptors. The high affinity for rat 5-HT2A receptors was retained when clavines even more simple in structure than 1b-3b, compounds 4b and 5b, were examined as 5-HT2A receptor antagonists. The nanomolar antagonist activity of simple clavines (1b-5b) in the rat suggests that the indolo[4,3-fg]quinoline system of the ergolines is the molecular fragment that is responsible for 5-HT2A receptor affinity, and not the substituent at position C-8.

Topics: Animals; Aorta, Thoracic; Arteries; Ergolines; Female; Guinea Pigs; Iliac Artery; In Vitro Techniques; Lysergic Acid; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tail

A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and alpha1-adrenergic receptors in rat aorta. In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues. It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial ago

Topics: Animals; Antipsychotic Agents; Arteries; Binding, Competitive; Ergolines; In Vitro Techniques; Inositol Phosphates; Male; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship

Acute experiments with dogs showed that irritation of the sympathetic trunk in the thoracic cavity is more likely to amplify than inhibit duodenal contractions. This stimulating effect is better seen with alpha- and beta-adrenoreceptors blocked by phentolamine hydrochloride and inderal and cannot be eliminated with dizergol used to block S1,2 receptors of the cellular membranes in smooth muscles. On the evidence and literary data it was deduced that the sympathetic trunk contains some serotoninergic nervous fibers potent to stimulate contractions of the duodenum.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adrenergic Fibers; Animals; Dogs; Duodenum; Ergolines; Female; Gastrointestinal Motility; Male; Muscle, Smooth; Phentolamine; Physical Stimulation; Pressure; Propranolol; Receptors, Adrenergic; Receptors, Serotonin; Serotonin Antagonists; Stimulation, Chemical

New glycosides derived from ergot alkaloids elymoclavine and DH-lysergol were synthesized by chemoenzymatic methods. beta-Glucosides were obtained either by chemical method or by transglycosylation (glycosidase from Aspergillus oryzae), lactosides were prepared by further extension of carbohydrate chain using beta-1,4-galactosyltransferase (bovine milk) and alpha-5-N-acetylneuraminyl-(2-->6)-beta-D-galactopyranosyl-(l-->4)-2- acetamido-2-deoxy-beta-D-glucopyranosyl-(1-->O)-elymoclavine was prepared using alpha-2,6-sialyltransferase (rat liver). Immunomodulatory activity of elymoclavine and 9,10-dihydrolysergol and their glycosylated derivatives on natural killer (NK) cell-mediated cytotoxicity of human resting and activated human peripheral blood mononuclear cells (PBMC) was investigated. Addition of ergot alkaloid glycosides to the mixtures of effector and target cells potentiated the PBMC cytotoxicity against both NK-sensitive and -resistant target cells. The glycoconjugates of elymoclavine enhanced cytotoxicity of PBMC against NK-resistant target cells. The glycoconjugates of DH-lysergol potentiated NK cytotoxicity of PBMC against NK-sensitive target cells.

Topics: Adjuvants, Immunologic; Animals; Carbohydrate Sequence; Cells, Cultured; Cytotoxicity, Immunologic; Ergolines; Ergot Alkaloids; Glycosides; Humans; Killer Cells, Natural; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Rats; Spectrometry, Mass, Fast Atom Bombardment; Tumor Cells, Cultured

5-Hydroxytryptamine elicits its physiological effects by interacting with a diverse group of receptors. Two of these receptors, the 5-HT1D beta and the 5-HT1E receptors, are approximately 60% identical in the transmembrane domains that presumably form the ligand binding site yet have very different pharmacological properties. Analysis of the pharmacological properties of a series of chimeric 5-HT1D beta/5-HT1E receptors indicates that sequences in the sixth and seventh transmembrane domains are responsible for the differential affinity of 5-carboxamidotryptamine for these two receptors. More detailed analysis shows that two amino acid differences in the sixth transmembrane domain (Ile333 and Ser334 in the 5-HT1D beta receptor, corresponding to Lys310 and Glu311 in the 5-HT1E receptor) are largely responsible for the differential affinities of some, but not all, ligands for the 5-HT1D beta and 5-HT1E receptors. It is likely that these two amino acids subtly determine the overall three-dimensional structure of the receptor rather than interact directly with individual ligands.

Topics: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Binding, Competitive; Chlorocebus aethiops; Cloning, Molecular; COS Cells; DNA Primers; Ergolines; Glutamic Acid; Humans; Isoleucine; Kinetics; Ligands; Lysine; Models, Structural; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; Protein Structure, Secondary; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Recombinant Fusion Proteins; Sequence Homology, Amino Acid; Serine; Serotonin; Transfection

Twelve ergolines (O-acylated lysergol and dihydrolysergol-I derivatives) were synthesized to study their antagonism of 5-HT responses in comparison with methylsergide and LY 53857 [6-methyl-1-(1-methylethyl)-8 beta-ergoline carboxylic acid 2-hydroxy-1-methylpropyl-ester hydrogen maleate] in cylindrical segments of the isolated rat tail artery. With regard to (9.10-didehydro-6-methyl-8 beta-ergoline)methyl R,S-2-methylbutyrate, the most potent new ergoline derivative, we examined the phenomenon of insurmountable antagonism to 5-HT by methylsergide. O-Acylated lysergol and dihydrolysergol-I derivatives competitively antagonized 5-HT-induced contractions with calculated pA2 values of 7.30 +/- 0.42 for the weakest and 8.42 +/- 0.35 for the most potent ergoline derivative in this series. N1-isopropyl substitution did not generally enhance 5-HT2 receptor affinities but lowered affinities for alpha 1 adrenoceptors in rat aorta. Methysergide and LY 53857 were insurmountable antagonists of 5-HT in rat tail artery. Preincubation with (9.10-didehydro-6-methyl-8 beta-ergoline)methyl R,S-2-methylbutyrate (1 mumol/l) partially prevented the depression of 5-HT-induced contractions caused by methysergide (1-10 nmol/l). Methysergide (100 nmol/l) abolished the protective effect of (9.10-didehydro-6-methyl-8 beta-ergoline)methyl R,S-2-methylbutyrate. (9.10-Didehydro-6-methyl-8 beta-ergoline)methyl R,S-2-methylbutyrate (1 mumol/l), concomitantly incubated with methysergide (30 nmol/l), partially restored the maximum response to 5-HT that had been depressed by methysergide (30 nmol/l). Partial restoration could not be mimicked by washout of methysergide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Ergolines; In Vitro Techniques; Lysergic Acid; Male; Methysergide; Muscle Contraction; Muscle, Smooth, Vascular; Phenylephrine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Regional Blood Flow; Serotonin Antagonists; Tail