N-SUBSTITUTION AND a,-ADRENERGIC RECEPTOR AFFlNITV OJi'LAUDANOSINE ANALOGUES
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Benzyltetrahydroisoquinoline (BTHIQ) molecules are able to adopt widely differing conformations that depend on the presence or absence of N-substituents. To assess the possible role of BTHIQ conformation on the afﬁnity of these compounds for α 1 -adrenergic receptors, of interest for the management of hypertension, the racemic N-unsubstituted BTHIQ norlaudanosine and a series of N-alkylated derivatives were assessed for binding to rat brain cortical sites labelled with the radioligand [ 3 H]prazosin. The α 1 -adrenergic afﬁnity in this series increased with the bulk of the substituent on the nitrogen atom, from the N-ethyl to the N-propyl analogue. Comparison of these results with published data for related BTHIQs and for the rigid mimics of the fully extended and semi-folded conformations of laudanosine, tetrahydropalmatine and glaucine, suggested that the α 1 -adrenergic receptor binding site is able to accommodate either conformation. The presence of a bulky substituent on the nitrogen atom seems to favor receptor binding independently of the favored conformation, and that the orientation in which BTHIQs are bound probably differs depending on the presence or absence of a hydroxyl group at a key position.
This work was supported by ICM grant Nº P99-031-F and by a research grant from the Generalitat Valenciana (GV01-292).
Quote ItemJ. Chil. Chem. Suc., Vol. 51, Nº3, 2006.