• Corpus ID: 29806656

Identical antagonist selectivity of central and peripheral alpha 1-adrenoceptors.

@article{Timmermans1981IdenticalAS,
  title={Identical antagonist selectivity of central and peripheral alpha 1-adrenoceptors.},
  author={Pieter B.M.W.M. Timmermans and F. Karamat Ali and H. Y. Kwa and Andreas Schoop and F P Slothorst-Grisdijk and Pieter A. van Zwieten},
  journal={Molecular pharmacology},
  year={1981},
  volume={20 2},
  pages={
          295-301
        }
}

• P. Timmermans, F. Ali, +3 authors P. V. van Zwieten
• Published 1 September 1981
• Biology, Chemistry, Medicine
• Molecular pharmacology

The present study was undertaken to test the relationship between binding affinity for alpha 1 -adrenoceptors and functional antagonism of drug-induced effects mediated by this type of alpha 1 -receptor sites for alpha -sympatholytic drugs. The radioligand [ 3 H]prazosin was used to identify alpha 1 -adrenoceptors in rat brain membranes. The specific binding of [ 3 H]prazosin was rapid, reversible, saturable, and of high affinity ( K D = 0.21 nM) and involved a single class of binding sites ( B max = 95 fmoles/mg of protein). A variety of alpha -adrenoceptor blocking drugs inhibited the specific binding of [ 3 H]prazosin (0.2 nM) according to sigmoid displacement curves from which the corresponding log IC 50 values were calculated. The binding sites of [ 3 H]prazosin in rat cerebral membranes possessed the characteristics of alpha 1 -adrenoceptors. Antagonists such as rauwolscine, tolazoline, yohimbine, and piperoxan, known as selective blocking drugs of alpha 2 -adrenoceptors, were found to be weak competitors. However, 2-[(29,69-dimethoxyphenoxyethyl)-aminomethyl]-1,4-benzodioxane (WB-4101) and unlabeled prazosin as well as two of its derivatives, 2-[4-(ethoxyethyloxy)-piperidine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-18,596) and 2-[4-(2-(1,4-benzodioxoyl))-piperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-33,274), which have been classified as antagonists preferably occupying alpha 1 -adrenoceptors, strongly interfered with this binding. The same alpha -adrenolytic drugs were studied with respect to their antagonism of (-)-phenylephrine-induced increases in diastolic pressure mediated via vascular, postsynaptic alpha 1 -adrenoceptors in pithed, normotensive rats. This antagonism was quantified with the aid of pA 2 values. For the alpha -adrenoceptor antagonists studied ( n = 21), the pA 2 in vivo correlated well with the log 1/IC 50 ( r 2 = 0.86). Similarly, a close relationship was calculated between the binding data and reported pA 2 values with respect to the antagonism of alpha 1 -adrenoceptor-mediated constrictor effects of the rabbit pulmonary artery in vitro ( r 2 = 0.90). The results demonstrate that the binding affinity in vitro of antagonists for alpha 1 -adrenoceptors corresponds with their functional antagonism of alpha 1 -adrenoceptors in vivo and in vitro . Moreover, these findings point to a similarity among peripheral and central alpha 1 -adrenoceptors.