Benzoquinolines and chloride secretion in murine colonic epithelium.
1. In all, 27 compounds related chemically to phenanthrolines were investigated for their ability to stimulate electrogenic chloride secretion in murine colonic epithelia under short circuit current conditions. A total of 11 compounds, not previously examined, were shown to have substantial activity. Cumulative concentration - response relations were obtained in the presence of amiloride to inhibit electrogenic sodium absorption and Ba(2+) to prevent potassium secretion. 2. Single- or double-ring substitutions in 1,10 phenanthroline (EC(50)=612 microM) produced only modest increases in affinity of between 0.7- and 2.1-fold. 3. Naphthalenes with either one or two ring nitrogens showed some activity but had very low affinity, yet some (e.g. isoquinoline, EC(50)=700 microM) were able to produce maximal responses. 4. Removal of one nitrogen from 1,10-phenanthroline or from 4,7-phenanthroline gave, respectively, 7,8-benzoquinoline and 5,6-benzoquinoline. These two were the most active compounds found, the EC(50) for 5,6-benzoquinoline being 29 microM. 5. Most concentration - response curves were steep with Hill slopes of approximately 3. At high concentration, some compounds inhibited the response, producing a characteristic bell shape. 6 5,6- and 7,8-benzoquinoline may be useful starting points for the synthesis of more potent agents by the addition of ring substituents.
Cuthbert
Alan W
AW
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5, Box 157, Hills Road, Cambridge, CB2 2QQ. awc1000@cam.ac.uk
D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051379:Mice
D016227:Benzoquinones; D002712:Chlorides