103009-41-2Relevant articles and documents
Centrally acting α1-adrenoceptor agonists based on hexahydronaphth[2,3- b]-1,4-oxazines and octahydrobenzo[g]quinolines
Nozulak,Vigouret,Jaton,Hofmann,Dravid,Weber,Kalkman,Walkinshaw
, p. 480 - 489 (1992)
Centrally acting α1-agonists may be of therapeutic value in dementias and other CNS disorders characterized by symptoms of noradrenergic insufficiency. Therefore, on the basis of known peripherally acting α1- agonists two new groups of centrally acting α1-agonists with improved lipophilicity, the hexahydronaphth[2,3-b]-1,4-oxazines type A and the octahydrobenzo[g]quinolines type B were designed. The N-methylated derivatives 14 and 33 demonstrate potent, direct agonistic activity at postjunctional α1-receptors. Ring substituent alterations in compounds of type A and B change the potency of compounds on the rabbit ear artery by over 3 orders of magnitude (pD2 = 5.35-8.40). The efficacy of these compounds varies from 42 to 110%. Those α1-agonists which were selective in the pithed rat increase vigilance in rats. Compound 14 was found to be a centrally acting α1-agonist with good tolerability in different animal species and in healthy volunteers. Furthermore, 14 selectively stimulates the breakdown of phosphatidylinositol in rat cerebral cortex slices. In vivo, the compound reverses behavioral deficits in animals which received noradrenergic lesions following DDC or DSP4 treatment. Oxazine 14 and its close derivatives are by far more lipophilic than commonly known α1-agonists. This is demonstrated in a ClogP-PROBIS plot.
