Tochergamine
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{{Infobox drug
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| image = Tochergamine.svg
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| routes_of_administration = Parenteral (e.g., intravenous injection, intramuscular injection)
| class = Oxytocic
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| PubChem = 43410827
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| ChemSpiderID = 37924316
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| synonyms = 621 I.S.; N,N-Diethyl-N′-(1,2,3,4-tetrahydronaphthyl)-glycinamide; Tochergamina
| IUPAC_name = N,N-diethyl-2-(1,2,3,4-tetrahydronaphthalen-1-ylamino)acetamide
| C=16 | H=24 | N=2 | O=1
| SMILES = CCN(CC)C(=O)CNC1CCCC2=CC=CC=C12
| StdInChI = 1S/C16H24N2O/c1-3-18(4-2)16(19)12-17-15-11-7-9-13-8-5-6-10-14(13)15/h5-6,8,10,15,17H,3-4,7,9,11-12H2,1-2H3
| StdInChIKey = SPTBJOUWQBBDDE-UHFFFAOYSA-N
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Tochergamine, also known as 621 I.S. or as N,N-diethyl-N′-(1,2,3,4-tetrahydronaphthyl)glycinamide, is an oxytocic drug related to ergometrine which does not appear to have been marketed.{{cite journal | vauthors = Campaigne E, Knapp DR | title = Structural analogs of lysergic acid | journal = Journal of Pharmaceutical Sciences | volume = 60 | issue = 6 | pages = 809–814 | date = June 1971 | pmid = 4942861 | doi = 10.1002/jps.2600600602 | quote = The tetrahydronaphthylamine derivative (XI) has been used clinically as an oxytocic (21). }}{{cite journal | vauthors = Garrett WJ, Embrey MP | title = A criterion for oxytocic activity; studies with tochergamine | journal = The Journal of Pharmacy and Pharmacology | volume = 10 | issue = 5 | pages = 325–327 | date = May 1958 | pmid = 13539807 | doi = 10.1111/j.2042-7158.1958.tb10309.x }}
It was reported to be effective as an oxytocic agent in animal studies, with oxytocic activity equivalent to that of ergometrine.{{cite journal | vauthors = Embrey MP | title = The action of drugs on the human uterus: tocograph studies | journal = Postgraduate Medical Journal | volume = 38 | issue = 435 | pages = 48–54 | date = January 1962 | pmid = 13890081 | pmc = 2482488 | doi = 10.1136/pgmj.38.435.48 | quote = In the case of another new synthetic, 'ergotlike' derivative, tochergamine, our experience was reversed. Found to exhibit oxytocic activity equal to that of ergometrine in experimental animals (Bovet-Nitti, 1952), tochergamine proved quite inactive when tested on the human intact uterus (Garrett and Embrey, 1958). }} In addition, the drug was reported to be effective in clinical studies at doses of 2 to 6{{nbsp}}mg parenterally. However, subsequent research found that it was inactive on the intact human uterus at doses of up to 20{{nbsp}}mg, and further investigation of tochergamine was abandoned.
Tochergamine has a simplified lysergamide-like chemical structure, with a 1-aminotetralin ring system, and is structurally related to lysergamides like ergometrine and LSD.{{cite journal | vauthors = Floss HG, Cassady JM, Robbers JE | title = Influence of ergot alkaloids on pituitary prolactin and prolactin-dependent processes | journal = Journal of Pharmaceutical Sciences | volume = 62 | issue = 5 | pages = 699–715 | date = May 1973 | pmid = 4574586 | doi = 10.1002/jps.2600620502 | quote = Only a limited amount of information is found in the literature on the relationship between the structure of ergot alkaloids and their activity as nidation inhibitors. Most of this information relates to the peptide-type ergot alkaloids. In early studies, Shelesnyak (81) found little activity for ergotamine (VIa) and its 9,10-dihydro derivative, for ergonovine (Vd) and methylergonovine (lysergic acid butanolamide), for tochergamine, a synthetic analog belonging to the ergotamine group, and for ergocristine (Vle) and its 9,10-dihydro derivative. }} However, it is not technically a partial ergoline or lysergamide, only partial ergoline-like, as its structural features differ in certain regards from those of ergolines and lysergamides. The oxytocic effects of lysergamides like ergometrine are thought to most likely be mediated by agonism of serotonin 5-HT2 receptors in uterine smooth muscle tissue.{{cite journal | vauthors = Schiff PL | title = Ergot and its alkaloids | journal = American Journal of Pharmaceutical Education | volume = 70 | issue = 5 | pages = 98 | date = October 2006 | pmid = 17149427 | pmc = 1637017 | doi = 10.5688/aj700598 | doi-broken-date = 1 July 2025 | quote = Ergonovine is a selective and moderately potent tryptaminergic receptor antagonist in various smooth muscles, being only a partially agonistic or antagonistic at tryptaminergic receptors in the central nervous system. In blood vessels the alkaloid is only weakly antagonistic of dopaminergic receptors and partitally agonistic of α-adrenergic receptors. The most pronounced effect of ergonovine is one of direct stimulation of the uterine smooth musculature, resulting in increased muscular tone and an enhancement of the rate and force of rhythmical contractions. This stimulant effect seems to be most closely associated with agonist or partial agonist effects at 5-HT2 receptors. [...] LSD and related hallucinogens are known to interact with brain 5-HT receptors to produce agonist or partial antagonist effects on serotonin activity. }}{{cite journal | vauthors = Vallera C, Choi LO, Cha CM, Hong RW | title = Uterotonic Medications: Oxytocin, Methylergonovine, Carboprost, Misoprostol | journal = Anesthesiology Clinics | volume = 35 | issue = 2 | pages = 207–219 | date = June 2017 | pmid = 28526143 | doi = 10.1016/j.anclin.2017.01.007 | quote = Methylergonovine is a serotonergic receptor agonist in the smooth muscle. It is also a weak antagonist of dopaminergic receptors and partial agonist of α-adrenergic receptors.22 Methylergonovine causes uterine contractions and relaxation at low doses, but causes sustained contractions and increased basal tone at high doses.24 The mechanism of action for uterine contraction is not well defined. Uterine contraction is likely produced by methylergonovine agonist effects on the 5-HT2 receptor found in uterine smooth muscle.22 Alternatively, methylergonovine could cause uterine contraction through direct stimulation of the α-adrenergic receptors in the uterus, which has been postulated to lead to calcium mobilization.25 }}
Tochergamine was first described in the scientific literature in 1951. It was developed by Daniel Bovet and colleagues at the Istituto Superiore di Sanità in Rome, Italy. The drug was known as tochergamina in Italy. It was clinically studied as an oxytocic agent in the 1950s.{{cite journal | vauthors = Sjostedt S | title = Tochergamina oder Methergin in der Nachgeburtsperiode? | journal = Gynaecologia | volume = 140 | issue = 6 | pages = 370–374 | date = December 1955 | pmid = 13294643 | doi = 10.1159/000308104 | trans-title = Tochergamina and methergin in afterbirth? | language = German | quote = In den letzten Jahren sind in Italien verschiedene Artikel erschie- nen über ein neues synthetisches Präparat mit kräftig uteruskontra- hierender Wirkung. Das Präparat ist von Bovet u. Mitarb. (1951) her- gestellt und am Istituto Superiore di Sanitå in Rom von Bovet-Nitti (1952) synthetisiert und pharmakologisch untersucht worden. Die chemische Bezeichnung ist N,N-diäthyl-N1-(2-tetrahydronaphthyl)- glycinamid-tartrat. Das Präparat trägt in Italien den Namen Tochergamina. }}{{cite journal | vauthors = Fabiano A | title = Azione ossitocica di un nuovo prodotto di sintesi, N,N-dietil-N'-(2 tetralil)-glicinammide (tochergamina) | journal = Quaderni di Clinica Ostetrica e Ginecologica | volume = 9 | issue = 4 | pages = 161–172 | date = April 1954 | pmid = 13186068 | trans-title = Oxytocic effect of a new synthetic product, N,N-diethyl-N'-(2-tetraethyl) glycinamide (tochergamine) | language = Italian }}Bravo, R. R. (1952). Clinical observations on the use of a new synthetic oxytocic drug: N2, N2-diethyl-N1-(1, 2, 3, 4-tetrahydronaphthyl) glycinamide (621 IS). Rend. Ist. Super. Sanita, 15, 1008. https://scholar.google.com/scholar?cluster=5046197701730900775 https://eurekamag.com/research/025/706/025706975.php "The activity of 621 I.S. was observed in 101 cases of normal or surgical birth. The drug is active in doses of 2-6 mg. given either intraven., intramusc, or intra-parietally. Given immediately after parturition it promotes expulsion of the placenta, causing a contraction of the uterus and controlling hemorrhage to within normal limits. Intraven. injn. of 2 mg. produces a prolonged rather than an immediate action and may be used prophylactically. The same dose intraven. is sufficient to obtain good hemostasis, at least in patients without unfavorable conditions (narcosis from ether, for example) in whom doses of 4 and 6 mg. are required. Intraparietal use is particularly important in cesarean section. In 11 cases the uterine reaction occurred in a more than satisfactory manner. In 3 cases in which 6 mg. was given intraven. there was pain in the hypogastric region following intense uterine contraction. The drug has a high margin of tolerance, does not change arterial pressure, and does not produce local effects."{{cite journal | vauthors = Bravo RR | title = Ensayo clínico del N,N-dietil-N'-(2-tetrahidor 1,2,3,4) naftil glicinamida | journal = Boletin. Sociedad Chilena de Obstetricia y Ginecologia | volume = 17 | issue = 1 | pages = 23–35 | date = April 1952 | pmid = 12977883 | trans-title = Clinical assay of N,N-diethyl-N'-(2-tetrahydro 1,2,3,4) naphthyl glucinamide | language = Spanish }}
Analogues of tochergamine, for instance the 2-aminotetralin positional isomer, have also been described, and have likewise shown oxytocic and lysergic acid-like activity.{{cite thesis | vauthors = Nichols DE | title = Potential Psychotomimetics: Bromomethoxyamphetamines and Structural Congeners of Lysergic Acid | date = May 1973 | publisher = University of Iowa | pages = 27,41–42 | oclc = 1194694085 | url = https://bitnest.netfirms.com/external/Theses/Nichols1973#page=36 | quote = Marini-Bettolo, Chiavarelli, Bovet, and co-workers (70-80) have tested over 200 derivatives of 1,2,3,4-tetrahydro-2-naphthylamine (2-aminotetralin) 23. This system is analogous to lysergic acid with the B and D rings removed. One of the derivatives 24 bore a striking resemblance to ergonovine and was a potent oxytocic with little vasomotor action (73). From their study of derivatives of 23, Marini-Bettolo, et al,(70) and Bovet, et al,(80) concluded that the 1,2,3,4-tetrahydro-2-naphthylamine element, rather than the indole moiety, in the structure of the ergot alkaloids is essential for sympatholytic activity. [...] Marini-Bettolo and co-workers (70) resolved the 2-aminotetralin derivative 37 and found that the dextro isomer possessed the lysergic acid-like activity. Although the signs of rotation were reported for 36 and 37, the absolute configurations were unknown at that time. More recent studies have shown that the phenylisopropylamines possess the R-(-) and the 2-aminotetralins possess the R-(+) absolute configuration (130, 131). Thus both 36 and 37 have the R configuration and correlate with lysergic acid. Although these agents have arisen from a search for better oxytocic agents, one may speculate that they reflect the action of the lysergic acid nucleus itself.}}