Putative benzodiazepine partial agonists demonstrate receptor heterogeneity.
This study explored whether the behavioral heterogeneity of benzodiazepine receptor (BDZR) ligands is a consequence of multiple receptor subtypes or partial agonism. Putative partial agonists Ro16-6028, Ro23-1590, Ro23-0364, and abecarnil were compared with U78875, a mixed agonist-antagonist, and CGS8216, an inverse agonist, in five BDZR-mediated functions: hyperphagia, anxiolysis, sedation, hypothermia, and anticonvulsant activity. Only abecarnil was an agonist in all end points. Each of the other drugs exhibited qualitatively different responses at these end points. Specifically, Ro23-0364 produced no effect on body temperature, but was an agonist at other tests. Ro23-1590 had no effect on anxiolysis and hypothermia, but was an agonist at other tests. In contrast to other putative partial agonists, Ro16-6028 was found to be an antagonist in sedation and U78875 was an antagonist in hypothermia, but both were agonists at other end points. These qualitative differences in activity in the five behavioral end points studied cannot be explained by partial agonism at a single receptor and indicate that these ligands differentially activate multiple BDZR subtypes.
Chen
S W
SW
Molecular Research Institute, Palo Alto, CA 94304, USA. Shuwen@Purisina.Molres.Org
Chen
H A
HA
Davies
M F
MF
Loew
G H
GH
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006963:Hyperphagia / Q000139:chemically induced; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D051381:Rats
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D001569:Benzodiazepines; D010433:Pentylenetetrazole