title: 1,3-Diamino-6,7-dimethoxyisoquinoline derivatives as potential alpha 1-adrenoceptor antagonists.
abstract: Treatment of 2-methyl-4,5-dimethoxybenzonitrile (3) with LDA followed by reaction with an N,N-disubstituted cyanamide provided a series of 1,3-diamino-6,7-dimethoxyisoquinolines (2), which were evaluated for alpha-adrenoceptor binding affinity and antihypertensive activity. 1-Amino-3-(dimethylamino)-6,7-dimethoxyisoquinoline (4) showed no significant affinity (Ki much greater than 10(-6) M) for alpha 1-adrenoceptors, while the corresponding 3-(2-furoylpiperazin-1-yl) analogue (8; Ki = 1.6 X 10(-7) M) was some 1000-fold less potent than prazosin. pKa data showed that N-2 protonation (34%) of 4 (pKa = 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 alpha 1-adrenoceptor. Computer-assisted comparison of the X-ray structures of 8 and prazosin suggested that the 4.0 kcal/mol difference in alpha 1-adrenoceptor 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 derives solely from alpha 1-adrenoceptor blockade.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D007546:Isoquinolines; D011942:Receptors, Adrenergic, alpha; D011224:Prazosin