Fatty Acid Derivatives of Clozapine Prolonged Antidopaminergic Activity of Docosahexaenoylclozapine in the Rat

Baldessarini, Ross J.; Campbell, Andrea Louise; Webb, Nigel L.; Swindell, Charles S.; Flood, James G.; Shashoua, Victor E.; Kula, Nora S.; Hemamalini, S

doi:10.1016/s0893-133x(00)00173-1

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…Indeed, only very few poses fulfilling the requirement of this interaction were obtained for compounds 1a – 1f and 2a – 2g . This is in line with reports that only certain substituents at the N5 position of clozapine are tolerated [ 22 , 51 ]. However Su et al [ 52 ] reported that the N5-clozapine derivative with a relatively large substituent ( o -TolSO 2 ) displayed dopamine D 2 receptor affinity of 63 nM, whereas the affinity of clozapine to this receptor is 208 nM.…”

Section: Resultssupporting

confidence: 93%

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

2016

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In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalent antagonists. Our approach was based on protein–protein docking, applying the Rosetta software to obtain populations of dimers as present in membranes with all the main possible interfaces. Consensus scoring based on the values and frequencies of best interfaces regarding four scoring parameters, Rosetta interface score, interface area, free energy of binding and energy of hydrogen bond interactions indicated that the best scored dimer model possesses a TM4–TM5–TM7–TM1 interface, which is in agreement with experimental data. This model was used to study interactions of the previously published dopamine D2 receptor homobivalent antagonists based on clozapine,1,4-disubstituted aromatic piperidines/piperazines and arylamidoalkyl substituted phenylpiperazine pharmacophores. It was found that the homobivalent antagonists stabilize the receptor-inactive conformation by maintaining the ionic lock interaction, and change the dimer interface by disrupting a set of hydrogen bonds and maintaining water- and ligand-mediated hydrogen bonds in the extracellular and intracellular part of the interface.Graphical AbstractStructure of the final model of the dopamine D2 receptor homodimer, indicating the distancebetween Tyr37 and Tyr 5.42 in the apo form (left) and in the complex with the ligand (right).Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-016-3065-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 93%

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

2016

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“…For example, DHA has been used as a prodrug conjugate with the antipsychotic clozapine to increase the brain‐to‐blood ratio of the drug. It is reported that chemical coupling of clozapine with DHA increased the brain‐to‐blood ratio of clozapine concentration by a factor of approximately 10 25…”

Section: Discussionmentioning

confidence: 99%

Accuracy of intraoperative imprint cytology for sentinel lymph node evaluation in the treatment of breast carcinoma

Cox

Centeno

Dickson

et al. 2004

Cancer

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“…Of course, the selected dopamine agonist should have a degree of "peripheral selectivity" to not neutralize the central antipsychotic effect. Another idea, at the preclinical stage, is to modify the brain penetrability of the active moiety by conjugating it to a fatty acid (Baldessarini et al, 2001). This concept has been used in animals for the atypical antipsychotic clozapine to decrease its peripheral adverse effects, and in principle, such an approach could be used for other drugs (Baldessarini et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats

Kapur¹,

Langlois²,

Vinken³

et al. 2002

J Pharmacol Exp Ther

147

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All atypical antipsychotics avoid extrapyramidal side-effects yet differ in their propensity to cause other side-effects, like prolactin elevation. We proposed that the atypical antipsychotics with a propensity for prolactin elevation would show a higher pituitary versus striatal D2 receptor occupancy. To investigate this hypothesis, we tested four atypical antipsychotics, two that are commonly associated with prolactin elevation (amisulpride and risperidone) and two that are less frequently associated (quetiapine and olanzapine). In particular, we calculated their ED 50 values to increase plasma prolactin and block peripheral pituitary D2 receptors to their ED 50 values to antagonize apomorphine-induced stereotypy and occupy central striatal D2 receptors. All antipsychotics dose dependently increased prolactin levels and antagonized apomorphine-induced stereotypy. However, the central to peripheral potency (ED 50 for apomorphine antagonism to ED 50 for prolactin elevation) differed remarkably across these drugs: amisulpride (21764), risperidone (14), quetiapine (10), and olanzapine (1.7). Compounds displaying a higher peripheral potency brought about higher prolactin levels for a given level of functional central antagonism. This dissociation between central and peripheral effects was explained by the differential occupancy of D2 receptors in the striatum versus in the pituitary [ratio of striatal/pituitary ED 50 values (milligram per kilogram) for D2 occupancy): amisulpride (17/0.026 ϭ 654), risperidone (0.89/0.081 ϭ 14), quetiapine (24/4.1 ϭ 6), olanzapine (0.30/0.43 ϭ 0.7). These results indicate that dissociation between central and peripheral D2 receptor occupancy is a major determinant of the degree of prolactin elevation observed at therapeutic doses.

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Fatty Acid Derivatives of Clozapine Prolonged Antidopaminergic Activity of Docosahexaenoylclozapine in the Rat

Cited by 8 publications

References 32 publications

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

Accuracy of intraoperative imprint cytology for sentinel lymph node evaluation in the treatment of breast carcinoma

The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats

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