1,3-Diamino-6,7-methoxyisoquinoline Derivatives as Potential α1-Adrenoreceptor Antagonists

Article abstract of DOI:10.1021/jm00400a026

Treatment of 2-methyl-4,5-dimethoxybenzonitrile (3) with LDA followed by reaction with N,N-substituted cyanamide provided a series of 1,3-diamino-6,7-dimethoxyisoquinolines (2), which were evaluated for α-adrenoreceptor binding affinity and antihypertensive activity. 1-Amino-3-(dimethylamino)-6,7-dimethoxyisoquinoline (4) showed no significant affinity (K_i >> 10^-6 M) for α₁-adrenoreceptors, while the corresponding 3-(2-furoylpiperazin-1-yl) analogue (8; K_i = 1.6 x 10^-7 M) was some 1000 fold less potent than prazosin. pK_a data showed that N-2 protonation (34percent) of 4 (pK_a = 7.1) would occur at physiological pH, in agreement with X-ray crystallographic analysis of 8*HCl.Comparison of positive charge distribution following protonation of 4 with the corresponding quinoline and quinazoline cations confirmed N-1 protonation is required for these heterocyclic nuclei to bind efficiently to the α₁-adrenoreceptor.Computer-assisted comparison of the X-ray structure of 8 and prazosin suggested that the 4.0 kcal/mol difference in α₁-adrenoreceptor binding energies was largely due to salt-bridge formation (ca. 3.0 kcal/mol) between the protonated quinazoline and the receptor protein.None of the isoquinolines (2) proved to be effective antihypertensive agents in rats even when administered at relatively high doses (10 mg/kg).These results support the hypothesis that the antihypertensive activity of prazosin, doxazosin, and related derivatives solely from α₁-adrenoreceptor blocade.