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Titolo:
PHARMACOLOGICAL CHARACTERIZATION OF BENZODIAZEPINE RECEPTOR LIGANDS WITH INTRINSIC EFFICACIES RANGING FROM HIGH TO ZERO
Autore:
MARTIN JR; SCHOCH P; JENCK F; MOREAU JL; HAEFELY WE;
Indirizzi:
F HOFFMANN LA ROCHE & CO LTD,DIV PHARMA,PRECLIN RES CH-4002 BASEL SWITZERLAND
Titolo Testata:
Psychopharmacology
fascicolo: 4, volume: 111, anno: 1993,
pagine: 415 - 422
Fonte:
ISI
Lingua:
ENG
Soggetto:
PARTIAL AGONIST; RO-16-6028; FLUMAZENIL; TOLERANCE; INVIVO; MICE;
Keywords:
BENZODIAZEPINE RECEPTOR LIGANDS; INTRINSIC EFFICACY; BRETAZENIL; FLUMAZENIL; DIAZEPAM; RO 41-7812; RO 42-8773; ANTAGONISM; PARTIAL AGONISM; ROTAROD DEFICIT; ANTEROGRADE AMNESIA; ANTICONFLICT; HYPERPHAGIA; ANTICONVULSIVE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
J.R. Martin et al., "PHARMACOLOGICAL CHARACTERIZATION OF BENZODIAZEPINE RECEPTOR LIGANDS WITH INTRINSIC EFFICACIES RANGING FROM HIGH TO ZERO", Psychopharmacology, 111(4), 1993, pp. 415-422

Abstract

Several benzodiazepine receptor ligands were pharmacologically characterized in a battery of functional tests after oral administration in mice, rats, and monkeys. Previous experiments have consistently demonstrated that diazepam exhibits high intrinsic efficacy, bretazenil exhibits intermediate intrinsic efficacy, Ro 42-8773 and Ro 41-7812 both show low intrinsic efficacy, and flumazenil exhibits virtually zero intrinsic efficacy. In the test battery used here it appears that nearly full intrinsic efficacy is required for clear anterograde amnesia or rotarod impairment. In contrast, full protection in the pentetetrazol test was achieved with intermediate-to-high intrinsic efficacy and nearly full protection with lower intrinsic efficacy. In the audiogenic seizure test full anticonvulsant effects were produced with intrinsic efficacy ranging from low to high. Clear inhibition of punished operant responding was observed for all test compounds except for Ro 41-7812 and flumazenil, which exhibit the lowest intrinsic efficacies. All of the test compounds enhanced palatable food consumption, with even thosehaving low intrinsic efficacy producing maximum effects approximatingthat of diazepam. By additionally taking into consideration the degree of receptor occupancy required to obtain pharmacological activity ineach of the tests in this battery it is possible to order the compounds with respect to intrinsic efficacy: diazepam > bretazenil > Ro 42-8773 > Ro 41-7812 > flumazenil. The latter four compounds all exhibiteda maximum antagonistic activity in tests involving reversal of meclonazepam- or flunitrazepam-induced central nervous system depression. Thus, using these tests appears to permit the accurate ordinal classification of benzodiazepine receptor ligands for intrinsic efficacy. This is considered important in view of the goal of optimal selection of novel compounds exhibiting only the minimum level of intrinsic efficacy necessary for a given therapeutic indication, thereby minimizing potential side effects.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 18:25:51