8-NH2-Boldine, an Antagonist of alA and a18 Adrenoceptors without Affinity for the alD Subtype: Structural Requirements for Aporphines at al-Adrenoceptor Subtypes
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2005-04-13Metadata
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Ivona, M. Dolores
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8-NH2-Boldine, an Antagonist of alA and a18 Adrenoceptors without Affinity for the alD Subtype: Structural Requirements for Aporphines at al-Adrenoceptor Subtypes
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Abstract
5tructure-activity analysis of 21 aporphine derivatives was performed
by examining their affinities for c10ned human alA. alB
and alD adrenoceptors (AR) using membranes prepared from
rat -1 fibroblasts stably expressing each a¡-AR subtype. AIl the
compounds tested competed for [I25I]-HEATbinding with steep
and monophasic curves. The most interesting compound was 8NHrboldine.
which retains the selective affinity for a¡A-AR
(pKi = 6.37 ± 0.21) vs. a¡B-AR(pKi = 5.53 ± 0.11) exhibited by
1.2.9,lO-tetraoxygenated aporphines. but shows low affinity for
alD-AR(pKi< 2.5). Binding studies on native adrenoceptors present
in rat cerebral cortex confirms the results obtained for human
c10ned a¡-AR subtypes. The compounds selective for the
alA subtype discriminate two binding sites in rat cerebral cortex
confirming a mixed population of a¡A- and a¡B-ARin this tissue.
AIl compounds are more selective as inhibitors of [W]-prazosin
binding than of [3Hj-diltiazem binding to rat cerebral cortical
membranes. A c10se relationship was found between affinities
obtained for c10ned a¡A-ARand inhibitory potencies on noradresubnaline-
induced contraction or inositol phosphate accumulation
in tail artery. confirming that there is a homogeneous functional
population of a¡A-ARin this vessel. On the contrary, a poor correlation
seems to exist between the affinity of 8-NH2-boldine for
c10ned alD-ARand its potency as an inhibitor of noradrenalineinduced
contraction or inositol phosphate accumulation in rat
aorta, which confirms that a heterogeneous population of a¡-AR
mediates the adrenergic response in this vessel.
Patrocinador
This work was funded by research grants from the Spanish Comisión
Interministerial de Ciencia y Tecnología SAF98-0123.
SAF2001- 2656 (PO).from the "Generalitat Valenciana" (GV01292)
and in part by the Presidential Chair in Science (BKC.Chile.
1996).
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Planta Medica, Vol. 71, p. 897-903, 2005
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