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10.1007 BF02146953

10.1007 BF02146953

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150 Speciatia EXt'ERIENTI&2412animals, particularly concerning the branched chainamino acids, may depend on the distinct mediating systemfor the transport of amino acids ~8. Further: the 'func-tional' temperature of the animal in deep hypothermia isabout 5 °C, whereas after spontaneous arousal, a stupen-dous physiologic effort, it is about 35 °C.
Zusammen/assung.
Die Serumkonzentration yon 21freien AminosAuren wurde bei Igeln im Winterschlaf, beispontanem Erwachen w/ihrend des Winterschlafs undnach dem Aufwachen im Friihling bestimmt. Mit Aus-nahme yon Valin, Leucin, Isoleucin und Tryptophansinken die Aminos~uren wAhrend des Schlafes signifi-kant ab und steigen beim Erwachen im Winter und Frtih-ling an.
R. KRISTOFF:ERSSON and SAARA BROBERG
Department o/ Physiological Zoology, University o/Helsinki (Finland), 12 September 7967.
~8 D. L. OXENDERand H. N.
CIIRISTENSEN, J.
biol. Chem.
238,
3686(1963).
Structure-Activity Relationship of Various Acylergoline (Dihydrolysergamine)
The natural ergot alkaloids and their derivatives havemanifold activities (adrenolytic, anti-5-hydroxytrypt-amine, spasmogenic, on central nervous system etc.). Ingeneral they are not very specific, for instance ergomet-fine, which is mainly oxytocic, causes also peripheral vaso-constriction, hyperthermia, and antagonizes 5-hydroxy-tryptamine (5-HT) ; ergotamine, which is mainly adreno-lytic, and methysergide (N-[ 1-(hydroxymethyl)-propyl]-1-methyl-o-lysergamide), which is mainly anti-5-HT,share also oxytocic and vasoconstrictor activities 1-3.The following is a brief outline of the structure-activity(oxytocic, anti-5-HT, and adrenolytic) relationship of anew series of acyl derivatives of
6-methyl-8fl-aminomethyl-
10~-ergoline (dihydrolysergamine) 4-9 in the attempt tofind compounds with a more specific activity. Thepharmacological properties of 1 of these derivatives, theacetyl-dihydrolysergamine (compound I) which hasspecific oxytocic activity, were further studied in com-parison with ergometrine and methergine (methylergo-metrine).
Structure-activity relationship o] carboxylic acid deriva-tives.
The nature of the acyl residue was found to influencestrongly the pharmacological activities of the parent com-pound (dihydrolysergamine). Compounds I, III, IV, VIII,XI and XXVI showed specific oxytocic activity compa-rable or superior to that of ergometrine, while compoundXXVIII showed high and specific adrenolytic activity.These findings contradict the general statement thatergoline derivatives are almost inactive oxytocics.Acylation of dihydrolysergamine yielded compounds(from I-XXlI) with a prominent oxytocic activity. Thisactivity, and the toxicity also, increased up to a certainpoint with the lengthening of the carboxylic aliphaticchain (I, VIII, XI). Longer chains (XIII, XIV, XV) orthe substitution of the aliphatic residue with an aromaticresidue (XVI, XX, XXI, XXII) caused marked reductionof the activity on the uterus. Hydroxylation in position10 (III and XIX) or methylation in 16 (IV and XVII)did not modify (but eventually reinforced) the specificoxytocic activity already present in the parent compounds(I and XVI). ~Vhen either Rx or R 4 were not hydrogen,
the
derivatives (II, IX, XII, V, VI, VII, X, and XVIII)lost the oxytocic properties of their parent compound (I,VIII, XI, and XVI). Nevertheless, methylation in posi-tion 1 afforded substances (II, IX, and XII) whichshowed prominent anti-5-HT and some adrenolyticproperties.
Derivatives of 6-methyl-8/5-aminomethyl-10ct-
Structure-activity relationship o/carbonic acid derivatives.
When R 3 was a carboalkoxy group, the compounds (from
XXlII-XXlX)
were found to be pharmacologically veryactive (as oxytocics, adrenolytics, and anti-5-HT) but lessspecific and more toxic than the acyl derivatives previouslydiscussed. Here again, the oxytocic activity disappearedwhen R 3 was an atiphatic chain with more than 4 carbonatoms, whereas the adrenolytic activity was not similarlyaffected and in one instance it became specific (compoundXXVIII).Methylation in N17 (R4) yielded an inactive compound(XXV), while methylation in N x strengthened the anti-5-HT activity (XXIV, XXVII, and XXIX) and left al-most unaltered the other properties. The introduction ofa hydroxyl group in position 10 yielded a compound withspecific oxytocic activity (XXVI).
All
the
lOfl-(cis
junction) analogues 5 of the most activecompounds here described were not reported in the Table,but were also examined and found to be inactive in allour tests.
Comparison between the pharmacological actions o/com-pound I, ergometrine, and methergine.
Since compound Ishowed a good specific oxytocic activity and a lowtoxicity, further pharmacological studies were performedon it in comparison with ergometrine and methergine.It was seen that its oxytocic activity on the uterus insitu was comparable qualitativeIy and quantitatively tothat of ergometrine and methergine. After small doses(0.02-0.1 mg/kg i.v.) it evoked contractions in silentuterus or increased in force and frequency those alreadypresent; after progressively larger doses, it caused firstforceful and tetanic contractions with increased restingtonus and then sustained contracture. The approximatex p. N. CHAMBERSand P. B.
MARSHALL, ,
Pharm. Pharmac.
79,
65(1967).E. ROTHLI~,Arch. exp. Path. Pharmak.
181,154
(1936).s j. R. GRAI~AM,The Practitioner t98, 302 (1967).4 L.
BERNARDI~
B.
CAMERINO~ B. PATELLI and S. REDAELLI~ Gazz.
chim. ital. 94, 936 (1964).5 L. BERNARDI,O. GOFFRI~DO nd B. PATELLI,Gazz. chim. ital.
94,
955 (1964).8 L. B~RNARDIand G. BosxsIo, Gazz. claim, tal.
94,
969 (1964).r Can. Patent 702,364, 19 Jan, 1965.8 Belg. Patent 618, 187, 17 Sept. 1962; Chem. Abstr. 59, 1698 (1963}.B. PArELLb personal communication.

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