Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids.

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Influence of different systems for feeding supplements to grazing dairy cows on milk fatty acid composition.

This study investigated the effects of different strategies for feeding supplements to grazing dairy cows on the proportions of fatty acids in milk. Two hundred and sixteen cows were fed supplementary grain and forage according to one of 3 different strategies; (1) CONTROL: cows grazed perennial ryegrass pasture (14 kg dry matter/d) supplemented with milled barley grain fed in the milking parlour and pasture silage offered in the paddock; (2) Partial mixed ration 1 (PMR1): same pasture allotment and supplement as CONTROL strategy, but the supplements presented as a mixed ration after each milking in feedpad, and; (3) Partial mixed ration 2 (PMR2): same pasture allotment, supplemented with a mixed ration of milled barley grain, alfalfa hay, corn silage and crushed corn grain fed in a feedpad. Within each strategy, cows were assigned to receive either 6, 8, 10 or 12 kg dry matter supplement/cow per d. Milk fatty acid proportions from cows fed CONTROL and PMR1 strategies were similar and different from those fed PMR2, particularly at 10 to 12 kg dry matter supplement/cow per d. The reduction in milk fat yield and concentration in cows fed high amounts of supplement as CONTROL and PMR1 was coincident with 4 × increase in 10t-18:1 proportion. The composition of the partial mixed ration (PMR) and the amount offered affected milk fatty acid proportions and milk fat content, however, the method of supplementation did not.

Ergot and its alkaloids.

This manuscript reviews the history and pharmacognosy of ergot, and describes the isolation/preparation, chemistry, pharmacodynamics, and pharmacotherapeutics of the major ergot alkaloids and their derivatives. A brief discussion of the hallucinogenic properties of lysergic acid diethylamide is also featured. An abbreviated form of the material found in this paper is presented in a 4-hour didactic format to third-professional year PharmD students as part of their study of vascular migraine headaches, Parkinson's disease, and naturally occurring hallucinogens/hallucinogen derivatives in the modular course offering Neurology/Psychiatry.

Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD).

Lysergic acid amides were prepared from (R,R)-(-)-, (S,S)-(+)-, and cis-2,4-dimethyl azetidine. The dimethylazetidine moiety is considered here to be a rigid analogue of diethylamine, and thus, the target compounds are all conformationally constrained analogues of the potent hallucinogenic agent, N,N-diethyllysergamide, LSD-25. Pharmacological evaluation showed that (S,S)-(+)-2,4-dimethylazetidine gave a lysergamide with the highest LSD-like behavioral activity in the rat two lever drug discrimination model that was slightly more potent than LSD itself. This same diastereomer also had the highest affinity and functional potency at the rat serotonin 5-HT(2A) receptor, the presumed target for hallucinogenic agents, and a receptor affinity profile in a panel of screens that was most similar to that of LSD itself. Both cis- and the (R,R)-trans-dimethylazetidines gave lysergamides that were less potent in all relevant assays. The finding that the S,S-dimethylazetidine gave a lysergamide with pharmacology most similar to LSD indicates that the N,N-diethyl groups of LSD optimally bind when they are oriented in a conformation distinct from that observed in the solid state by X-ray crystallography. The incorporation of isomeric dialkylazetidines into other biologically active molecules may be a useful strategy to model the active conformations of dialkylamines and dialkylamides.