Synthesis, pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides.

Abstract Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6 H -benzofuro[2,3- e ]pyrido[1,2- a ][1,3]diazepin-12-ium chloride ( 8a ), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6 H -benzofuro[2,3- e ]pyrido[1,2- a ][1,3]diazepin-12-ium chloride ( 8c ) and 3-methoxy-11-methyl-6-oxo-7,13-dihydro-6 H -benzofuro[2,3- e ]pyrido[1,2- a ][1,3]diazepin-12-ium chloride ( 8e ) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a , 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L 1 , H 1 and A 2 sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the α1 isoform of the GABA A /BzR (L Di interaction) but are non-selective for α5 (no L 2 interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the α1 receptor although not very potent ( K i  = 746.5 nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with α1 selectivity.