Arylalkylamine-, beta-carboline-, quinolizine- and azecine-derived compounds and their in vitro interaction with the ionotropic 5-HT3 receptor: search for new lead structures.
Specific serotonin receptor agonists and antagonists are marketed with respect to various diseases, most prominently severe emesis. To identify new chemical classes with affinity for the serotonin 5-HT3 channel, several compounds were synthesized which can be structurally classified as arylalkylamines, azecines, quinolizines and beta-carbolines. These were tested in three models: (1) direct effect on ileum (overall model for contracting or relaxant effect), (2) antiserotoninergic effects on rat ileum (crude serotonin model), (3) inhibitory effect on the 5-HT, receptor channel complex expressed in N1E-115 cells (serotonin-induced [14C]guanidinium influx (specific model)). Key findings and conclusion: Several azecine-type compounds exhibit 5-HT3 receptor channel antagonistic properties at concentrations close to that of tropisetron (used as a positive control) and might serve as potential lead structures for the development of further 5-HT3 channel receptor antagonists.
Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität, Jena, Germany. ch.enzensperger@googlemail.com
Christoph
C
Enzensperger
Jochen
J
Lehmann
Katrin
K
von Schroetter
Anja
A
Riyazi
Eugen J
EJ
Verspohl
D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D055808:Drug Discovery; D005260:Female; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019791:Guanidine / Q000378:metabolism; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D011807:Quinolizines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000077526:Tropisetron
D000588:Amines; D002243:Carbolines; D002412:Cations; D005765:Gastrointestinal Agents; D007211:Indoles; D011807:Quinolizines; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D000077526:Tropisetron; D019791:Guanidine