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Behavioral and neurochemical profiles of discriminant benzamide derivatives

Published online by Cambridge University Press:  28 April 2020

P. Sokoloff ,
M.-P. Martres ,
K. Redouane ,
J.-C. Schwartz ,
P. Protais ,
M. Vasse ,
I. Dubuc ,
J. Costentin ,
P. Hamdi  and
A. Mann
...Show all authors
P. Sokoloff
Affiliation:
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM, 2 ter rue d’Alésia, 75014Paris, France
M.-P. Martres
Affiliation:
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM, 2 ter rue d’Alésia, 75014Paris, France
K. Redouane
Affiliation:
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM, 2 ter rue d’Alésia, 75014Paris, France
J.-C. Schwartz*
Affiliation:
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM, 2 ter rue d’Alésia, 75014Paris, France
P. Protais
Affiliation:
UA 1170 du CNRS, Unité de Neuropsychopharmacologie Expérimentale, U.E.R. de Médecine et Pharmacie, Avenue de l’Université, 76800St-Etienne du Rouvray, France
M. Vasse
Affiliation:
UA 1170 du CNRS, Unité de Neuropsychopharmacologie Expérimentale, U.E.R. de Médecine et Pharmacie, Avenue de l’Université, 76800St-Etienne du Rouvray, France
I. Dubuc
Affiliation:
UA 1170 du CNRS, Unité de Neuropsychopharmacologie Expérimentale, U.E.R. de Médecine et Pharmacie, Avenue de l’Université, 76800St-Etienne du Rouvray, France
J. Costentin
Affiliation:
UA 1170 du CNRS, Unité de Neuropsychopharmacologie Expérimentale, U.E.R. de Médecine et Pharmacie, Avenue de l’Université, 76800St-Etienne du Rouvray, France
P. Hamdi
Affiliation:
Centre de Neurochimie, Laboratoire de Pharmacochimie Moléculaire, ERA 393 du CNRS, Strasbourg, France
A. Mann
Affiliation:
Centre de Neurochimie, Laboratoire de Pharmacochimie Moléculaire, ERA 393 du CNRS, Strasbourg, France
C.G. Wermuth
Affiliation:
Centre de Neurochimie, Laboratoire de Pharmacochimie Moléculaire, ERA 393 du CNRS, Strasbourg, France
*
Corresponding author: J.-C. Schwartz Correspondance à adresser à
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Summary

Discriminant benzamide derivatives (DBD), the prototype of which is DO 710 i.e. N- [(1-propyl 2-pyrrolidinyl) methyl] 5-methyl sulfamoyl 2-methoxy benzamide, were compared to classical neuroleptics such as haloperidol in various behavioral and biochemical tests. Whereas the ID50 (or ED50) of haloperidol for antagonising various apomorphine-induced behavioral responses and producing catalepsy in rats were all around 0.1 mg/kg. DO 710 clearly distinguished catalepsy, HVA increase and apomorphine-induced licking and sniffing in rats (for which the ED50 (or ID50) were 13-54 mg/kg) from apomorphine-induced climbing, yawning and hypothermia (for which the ID50 were 1-2 mg/kg) (fig. 1, 2 and 4). Moreover, DO 710 and other DBD potentiated stereotypies in mice, whereas haloperidol and other classical neuroleptics did not (fig. 3). These features do not seem to be attributable to a heterogenous distribution of DBD in brain, since their ED50 for HVA increase and for inhibiting 3H-N-propylnorapomorphine binding in vivo did not differ in striatum and in limbic regions.

In in vitro binding experiments, DO 710 and other DBD discriminated two classes of 3H-domperidone binding sites in striatum, whereas only one component with a relatively low affinity for DBD could be detected in pituitary (fig.5-6, Table 3). 3H-DO 710 allowed charaterization of a D-2 site with a low affinity for DBD, which was fully sensitive to GTP regulation and present in pituitary and brain, and of a “D-4” site, preferred by DBD, which was little or not sensitive to GTP, present in brain and particularly enriched in olfactory bulb but absent in pituitary (fig. 7). 3H -azidosulpride (i.e. N-[(1-3H- propyl 2-pyrrolidinyl) methyl] 2-methoxy 4-azido 5-methylsulfamoyl benzamide), a photoactivable analog of 3H-DO 710, was used for irreversible labelling of dopamine recognition sites. When subjected to SDS-PAGE, receptor from striatum, pituitary and olfactory bulb co-migrated as a single band of 85 kDa (fig. 8).

These results may suggest the existence of two subclasses of dopamine D-2 receptor as targets for neuroleptic actions, one being preferred by DBD. The recognition subunits of these receptors have similar apparent molecular size.

Résumé

Résumé

Les dérivés benzamides substitués discriminants (DBD) dont le prototype est le DO 710 : N- [(propyl-1 pyrrolidinyl-2) méthyl] méthoxy-2 méthylsulfamoyl-5 benzamide, ont été comparés à des neuroleptiques classiques comme le halopéridol dans divers tests comportementaux et biochimiques. Alors que les DE50 (ou DI50) du halopéridol pour antagoniser les réponses comportementales induites par l’apomorphine et pour produire la catalepsie chez le rat sont toutes voisines de 0.1 mg/kg, le DO 710 distingue clairement la catalepsie, l'augmentation d'HVA et les léchements et reniflements chez le rat (pour lesquels les DE50 (ou DI50) sont de 13 à 54 mg/kg) de la verticalisation, des baillements et de l’hypothermie induits par l’apomorphine (pour lesquels les DI50 sont de 1 à 2 mg/kg) (Fig. 1, 2 et 4). Le DO 710 et d’autres DBD potentialisent les stéréotypies chez la souris, alors que les neuroleptiques classiques n’ont pas cette propriété (Fig. 3). Ce profil pharmacologique original des DBD ne semble pas être du ci une distribution hétérogène de ces composés dans le cerveau, car leur DE50 Pour accroître l'HVA et pour inhiber la liaison in vivo de N propylnorapomorphine - 3H ne different pas dans le striatum et les régions limbiques.

Dans les études de liaison in vitro, le DO 710 et les DBD discriminent deux populations de sites de liaison du dompéridone - 3H dans le striatum, alors que seule la population de sites à basse affinité pour les DBD est détectable dans l’hypophyse antérieure (Fig. 5, 6 et Tableau 3).

Le DO 710-3H a permis de caractériser un site D-2 à relativement basse affinité pour les DBD, complètement sensible à la régulation par le GTP, présent dans l'hypophyse et le cerveau et un site “D-4”, présentant une meilleure affinité pour les DBD, peu ou pas sensible au GTP, présent dans le cerveau et plus particulièrement enrichi dans le bulbe olfactif mais absent de l’hypophyse (Fig. 7).

L’azidosulpride -3H i.e. N-[(propyl -3H-1 pyrrolidinyl - 2)méthyl] méthoxy-2 méthylsulfamoyl-5 azido-4 benzamide, un analogue photoactivable du DO 710 a été utilisé pour marquer irréversiblement les récepteurs dopaminergiques. Les récepteurs du striatum, de l’hypophyse et du bulbe olfactif ainsi marqués et soumis à une électrophorèse en SDS sur gel de polyacrylamide co-migrent en une seule bande de 85 KDa (Fig. 8).

Ces résultats suggèrent l'existence de deux sous-types de récepteurs dopaminergiques D-2, dont le blocage préférentiel de l’un d’entre eux par les DBD explique leurs propriétés particulières. Les deux récepteurs ont un site de reconnaissance de taille moléculaire apparente identique.

Keywords

D-2 dopamine receptorsBenzamideBehaviorLigand binding assayPhotoaffinity labellingRécepteurs dopaminergiques D-2Dérivé benzamideComportementLiaison in vitroMarquage par photoaffinité
Type
Research Article
Information
Psychiatry and Psychobiology , Volume 2 , Issue 4 , 1987 , pp. 253 - 263
Copyright
Copyright © European Psychiatric Association 1987

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