Centrally acting α1-adrenoceptor agonists based on hexahydronaphth[2,3- b]-1,4-oxazines and octahydrobenzo[g]quinolines

Article abstract of DOI:10.1021/jm00081a008

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.