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agonist selectivity of mono- and dihydroxy-2-N,N-DI-n-propylaminotetralins

1984; Elsevier BV; Volume: 97; Issue: 1-2 Linguagem: Inglês

10.1016/0014-2999(84)90512-0

1879-0712

Pieter B.M.W.M. Timmermans, Marie-Jeanne Mathy, Bob Wilffert, Hans O. Kalkman, Gerard Smit, Durk Dijkstra, Alan S. Horn, Pieter A. van Zwieten,

Food Quality and Safety Studies

The pressor activities and the identity of the postjunctional α-adrenoceptors involved were determined for a series of congeneric mono- and dihydroxy-substituted 2-N,N-di-n-propylaminotetralins and N,N-di-n-propyldopamine (DPDA) following i.v. administration to pithed normotensive rats. The affinity for α1- and α2-adrenoceptor-like binding sites was obtained from radioligand displacement studies. The 5- and 7-OH substituted tetralins as well as DPDA were reasonably potent and about equieffective pressor agents. The 6-OH congener had almost no vasoconstrictor effects whereas the 8-OH positional isomer occupied an intermediate position. The 5,6- and 6,7-di-OH analogs very effectively raised the diastolic pressure of pithed rats. On account of the inhibition exerted by prazosin (0.1 mg/kg) and yohimbine (1 mg/kg) the 5- and 7-OH isomers as well as DPDA can be classified as mixed α1α2-adrenoceptor agonists, the α1-adrenoceptor-stimulating potency being more pronounced especially for the 5-OH congener. In addition, a significant contribution of serotonin receptors to the pressor responses to the 8-OH compound was detected. Similarly, α2-adrenoceptors were mainly responsible for the vasoconstriction caused by the 6,7-di-OH isomer, whereas the 5,6-di-OH congener very selectively stimulated this α2-type receptor in the lower dose range and α1-adrenoceptor stimulation predominated at higher doses of this agonist. The 6,7-di-OH compound failed to activate vascular postjunctional β2-adrenoceptors. The results indicate that the α1α2-adrenoceptor agonist selectivity depen on the position(s) and the number of hydroxy groups present as well as on the alkyl substitution at the amino function. 2-N,N-Di-n-propylamino-6,7-dihydroxytetralin may be a more suitable α2-adrenoceptor selective agonist than M-7.