A number of O- and N-alkylated derivatives of the antinociceptive, orally active, mu-opioid-selective truncated enkephalin analog L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide (2, SC-39566) were synthesized to explore the structure-activity relationships of the series. The parent molecule is quite forgiving of substitution on the tyrosyl phenolic moiety and on the alanyl nitrogen. The tyrosyl and (phenylpropyl)amide NH sites, however, appear to be critical to interactions with the receptor, for even modest changes at these sites cause great loss of binding potency.
The phenyl o-radical formed by reduction of aryl halides in an aprotic solvent undergoes efficient radical substitution on an adjacent benzene ring. Several examples of this cyclisation reaction are given. The reaction is appropriate for the synthesis of 6-membered aromatic rings where the two reacting phenyl groups are held in a cis-configuration by an olefin bond or another aromatic ring.
A series of tricyclic pyrazoles were prepared from intermediates available from steroid total synthesis and tested for antiarrhythmic and antiinflammatory activity.
Enkephalin Analogues as Systemically Active Antinociceptive Agents: O-and N-Alkylated Derivatives of the Dipeptide Amide L-2,6-Dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide (Ia).-A series of differently modified derivatives (18 examples) of the enkephalin analogue (Ia) such as (Ib) to (If) is synthesized and investigated with respect to antinociceptive activities and opioid competitive binding properties. The NH-sites of the tyrosyl and ( phenylpropyl)amide moieties appear to be essentially for the interaction with the receptor, as indicated by the inactivity of (Id) and (If). On the other hand, the modifications of the alanyl nitrogen in (Ie) and the tyrosyl phenolic residue in (Ib) and (Ic) lead to no or only little change in activity. -(PITZELE, B. S.; HAMILTON, R. W.; KUDLA, K. D.; TSYMBALOV, S.; STAPELFELD, A.; SAVAGE, M. A.; CLARE, M.; HAMMOND, D. L.; HANSEN, D. W. JUN.; J. Med. Chem. 37 (1994) 7, 888-896; Dep. Chem. Neurol. Dis. Res., Skokie, IL 60077, USA; EN)
Zu pharmakologischen Untersuchungen werden über 100 tricyclische Pyrazole derallgemeinen Strukturen (V), (VI), (IX) und (X) nach an sich bekannten, mit guten Ausbeuten verlaufenden Verfahren hergestellt.
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