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The alkaloids coclaurine and tetrandrine (an N- and O-methylated dimeric coclaurine) are know
as vascular smooth muscle relaxants whose action is attributed to a greater or lesser degree to the
blockage of potential-operated calcium channels or #1-adrenergic receptor antagonism. As
coclaurine represents the “eastern” half of the tetrandrine molecule, it was used as a template on
which substituents were appended to simulate the conformation and structure of the dimer.
Selective radioligand displacement experiments were performed to determine the affinities for #
1-adrenergic receptors and for the benzothiazepine binding locus in the voltage-gated calcium
channel, as well as functional studies on the relaxation of rat aorta rings contracted by
noradrenaline or KCl. The behavior of a set of 10 N - and O-methylated coclaurine derivatives
was studied, and also of 9 derivatives with benzyl ether functions which could be regarded as
simplified analogs of tetrandrine. Conformational studies of these derivatives, carried out by
NMR, indicated that the alkylation of the tetrahydroisoquinoline nitrogen in these compound
makes them adopt a preferentially “folded” conformation in solution, close to that in which the
“eastern” half of the tetrandrine molecule is held. The results of affinity studies, in agreement
with the results for vascular smooth muscle relaxant activity, indicate that an increase in the
extent of methylation in the N- and O-methylated derivatives of coclaurine causes a decrease in
adrenergic antagonism and an increase in calcium channel blockage. The derivatives with
aromatic residues exhibited similar behavior to tetrandrine: most of them show good affinity and
potency regarding their vascular relaxant activity related to adrenergic receptor antagonism or
the modulation of calcium channel function. Some of these derivatives proved to be more potent
vasorelaxants then tetrandrine itself.
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Los alcaloides coclaurina y tetrandrina (una coclaurina dimérica N- y O- metilada) son conocidos
relajantes de la musculatura lisa vascular, cuya acción se atribuye en mayor o menor grado al
bloqueo de canales de calcio dependientes de voltaje o al antagonismo de receptores
#1-adrenérgicos. Ya que la coclaurina representa a la mitad “oriental” de la molécula de
tetrandrina, se realizaron modificaciones sobre ésta de manera de simular la conformación y
estructura del dímero. Se realizaron ensayos de desplazamiento de radioligandos selectivos para
estudios de afinidad por receptores #-adrenérgicos y por el sitio benzotiacepínico en el canal de
calcio dependiente de voltaje, además de estudios funcionales de relajación de contracciones
inducidas por noradrenalina o KCl en aorta de rata. Se estudió el comportamiento de un conjunto
de 10 análogos N- y O-metilados de coclaurina, además de 9 derivados con funciones bencil éter
que pudieran considerarse como análogos simplificados de tetrandrina. Estudios
conformacionales de los derivados realizados por RMN, indican que la alquilación del nitrógeno
tetrahidroisoquinolínico en estos compuestos les hace adoptar una conformación
preferencialmente “plegada” en solución, próxima a la que mantiene la mitad “oriental” de la
tetrandrina. Los resultados de estudios de afinidad, en concordancia con los resultados de
relajación de la musculatura vascular, indican que el aumento en el grado de metilación para los
derivados N- y O-metilados de coclaurina produce una disminución del antagonismo adrenérgico
y un aumento del bloqueo sobre el canal de calcio. Los derivados con residuos aromáticos
mostraron el mismo comportamiento que la tetrandrina: la mayoría presenta buena afinidad y
potencia en cuanto a su la actividad relajante vascular relacionada con el bloqueo de los
receptores adrenérgicos o del canal de calcio. Algunos de los derivados resultaron ser más
potentes relajantes del tejido vascular que la misma tetrandrina.
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