Some Pharmacological Actions of D-lysergic acid methyl carbinaolamide
Glasser, A
Nature 1961 189:313-314
D-lysergic acid methyl carbinaolamide, C(18)H(21)N(3)O(2), is a new alkaloid produced by a strain of Claviceps Paspali Stewens and Hall. Arcamone, Bonino, Chain, Ferretti, Pennella, Tonolo and Vero (
1) isolated the new alkaloid from submerged cultures and determined its structure. I have now investigated some of the pharmacological actions of the new alklaoids.
D-Lysergic acid methyl carbinolamide was kindly supplied to me by Prof. E. B. Chain. Freshly prepared aqueous solutions of the maleate salt (C(18)H(21)N(3)O(2).C(4)H(4)O(4)) were used in my experiments.
The intravenous LD50 of the new alkaloid was approximately 150mgm./kgm for mice and 0.75 mgm./kgm. for rabits/ Before death, the mice showed periodic convulsions of a clonic type, erection of the hairs and excitability. At doses of 50-100mgm./kgm. it produced only this peculiar symptomatology: the mice stood upright and pressed on each other's noses and chattered their teeth. In rabbits, and injection into the ear vein in doses of 0.1-1mgm./kgm. produced dilatation of the pupil, excitability or convulsions of a clinic type. The ears became pale and cold with intense vaso-constirction. The toxicity of the alkaloid to rabbits seemed to depend on its power of raising the body-temperature in this species. In rabbits the similarity between the effects of the new alkaloid and ergometrine were particularly striking, but ergometrine was less toxic to rabbits (the approximate intravenous LD50 of ergometrine was 3.5mgm./kgm.).
D-lysergic acid methyl carbinolamide induced, in low concentrations (minimum active concentration 0.1-1µgm./ml.), a contracture in the isolated uterus of the virgen guinea pig. There was a satisfactory dose/response relationship. Tgus contracture was very similar to that produced by ergmetrine maleate, which, however, was 1-2 times more potent.
On the rabbit uterus in situ both alkaloids produced a prompt contraction and increased rhythmic activity of the uterus. For ergometrine the minimum active dose by intravenous route was 0.1-0.3 mgm./kgm. and for the new alkaloid 0.2-0.5mgm./kgm. The actions of both alkaloids lasted some minutes, and owing to the favourable circumstance that the interference between the effects of the two alkaloids was negligible, it was possible to test them on the same preparation. Ergometrine was 1-2 times more potent than the new alkaloid.
On the isolated seminal vesicles of the guinea puig, the new alkaloid was approximately 200 times less potent than ergotamine tartrate as an adrenergic blocking drug.
Rabbits anaethetized with urethane supported doses of D-lysertgic acid methyl carbinolamide which would have killed unanaesthetized animals. Rapid intravenous injections of small doses (0.1-0.2mgm./kgm.) of the new alkaloid caused an evanescent decrease or a small increase of blood pressure; with higher doses (0.3/0.5mgm./kgm. and more) the blood pressure increased moderately without showing any dose/response relationship. Ergometrine maleate seemed to be less active on bloodpressure, and there was no significant change of blood pressure with 0.3-0.5 mgm./kgm.
The new alkaloid was without effect, when given in small doses, on the blood pressure of cats anaethetized with chloralose. Higher intravenous doses (0.1-0.3mgm./kgm.) caused a sustained hypotension of long duration and a moderate decrease of heart-rate. The respiration of rabbits and cats was depressed by small doses of the new alkaloid; cats seemed to be less resistant than rabbits. In cats, 0.01mgm./kgm. of the new alkaloid caused broncho-constriction and contractions of the nictitating membrane of long duration.
The new alkaloid have no action on isolated rabbit auricles at doses up to 100µgm./ml.
In summing up, the new naturally occuring alkaloid D-lysergic acid methyl carbinolamide has powerful ergometrine-like oxytocic action and weak ergotamine-like adrenergic blocking actions. It must be included, on the basis of pharmacological evidence, in the ergometrine group of ergot alkaloids. Ergometrine, however, is less toxic and more active than the new alkaloid. Some of my results suggest that it could have a lysergic acid diethylamide-like activity, but this hypothesis must be checked by experiments on humans.
Full details of this work will be published elsewhere.
