The in vitro effects of benzodiazepines on the rat diaphragm. Structure-activity relationships.
The effect of three different subgroups of benzodiazepines on the indirectly evoked twitch tension was investigated in the in vitro rat phrenic nerve - hemidiaphragm preparation. Two effects were observed: an initial increase in twitch tension at lower concentrations with some benzodiazepines, and a concentration-dependent depression at higher concentrations with all benzodiazepines. Significant differences for these effects were observed among the three subgroups of benzodiazepines and additionally within the subgroup of the 1,4-benzodiazepine-2-ketones. Structural requirements for both effects were different. For the increase of twitch tension a --CH3 substitution at R1 and a --F substitution at R2' were beneficial. For the twitch depression an --OH substitution at R3 and a --C1 substitution at R2' were optimal. An interaction between substituents at different substitution sites occurred. The potency of twitch depression showed a good correlation with literature reports of pKa values and a poor-to-inverse correlation with lipophilicity indices. A benzodiazepines antagonist, Ro 15-1788, caused no change in twitch tension in the concentration range of the investigated benzodiazepines nor did it prevent the twitch depression caused by benzodiazepines.
Driessen
J J
JJ
Van Egmond
J
J
Vree
T B
TB
Booij
L H
LH
Crul
J F
JF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects; D005442:Flumazenil; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects; D010791:Phrenic Nerve / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D005442:Flumazenil