Novel olanzapine analogues presenting a reduced H1 receptor affinity and retained 5HT2A/D2 binding affinity ratio

Jafari, Somayeh; Bouillon, Marc E.; Huang, Xu‐Feng; Pyne, Stephen G.; Fernandez, Francesca

doi:10.1186/1471-2210-12-8

Cited by 14 publications

(8 citation statements)

References 46 publications

(42 reference statements)

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“…This study supports the potential role of H 1 receptor affinity in antipsychotic-induced weight gain and fat deposition. As shown in our previous report [27] , OlzEt and OlzHomo have a lower affinity for binding to the H 1 receptors ( K i = 1.95, and K i = 13.63, respectively) compared to that of Olz ( K i = 0.13). Therefore, the pronouced antagonism of OlzEt and OlzHomo at the H 1 receptors may be responsible for their significantly attenuated propensity to induce weight gain and metabolic dysfunction, which are associated with Olz treatment.…”

Section: Discussionsupporting

confidence: 62%

“…This effect may be prevented by 5HT 2A antagonism by Olz at the level of motor pathways in the spinal cord or in the brain [61] . In our previous study [27] , OlzEt showed a similar affinity as Olz for blocking the D 2 and 5HT 2A receptors in the striatum and prefrontal cortex respectively, which may partly explain the way in which OlzEt inhibits the PCP-induced behaviours in vivo . On the other hand, OlzHomo demonstrated a lower affinity for blocking these two receptors, which may contribute to its lack of efficacy for alleviating the PCP-induced hyperactivity.…”

Section: Discussionmentioning

confidence: 67%

“…We have previously examined two new analogues of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10 H benzo[ b ]thieno[2,3- e ] [1] , [4] diazepine) [68] , and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10 H -benzo[ b ]thieno[2,3- e ] [1,4]diazepine) (newly synthesised by our research group) [27] , presenting an ethyl substituent at position 2 of the thiophene ring of Olz compounds. We have demonstrated in our previous published study [27] that both of these analogues showed an in vitro lower affinity for the H 1 receptors while maintaining similar affinities for the D 2 and 5HT 2A receptors when compared to Olz. Since the blockade of the H 1 receptors has been repeatedly described as the most likely mechanism for atypical antipsychotic drug-induced weight gain, the present study further explored the therapeutic potential in vivo of these two analogues of Olz in an animal model of schizophrenia while assessing their metabolic side effects.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

et al. 2013

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Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

et al. 2013

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“…Olanzapine (OZ), an antipsychotic drug for treating brain diseases, was apt to be pumped out by P-gp in blood-brain barrier (BBB) and metabolized by first-pass effect, which suffer9ed great loss before reaching the desired sites and led to low brain permeability (Altamura et al, 2003;Srivastava & Ketter, 2011;Jafari et al, 2012). Based on the unique physical contact of nasal cavity and cranial cavity in the anatomy, nasal mucosal delivery could facilitate drugs across BBB conveniently and effectively by avoiding first-pass metabolism, bypassing efflux of P-gp and reducing the side effects.…”

Section: Mms Strategy For Nasal Drug Deliverymentioning

confidence: 99%

Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery

Yang

et al. 2016

Drug Delivery

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Amphiphilic block copolymers-based mixed micelles established as new drug-loading system showed superior characteristics in delivering drug such as improved solubility, enhanced stability, multifunctional carrier materials, targeting ability, and high bioavailability. Recently, there are increasing focuses on exploration and study of noninvasive routes, and the results present perfect feasibility, improved compliance and fewer aches and pains. The aim to apply mixed micelles to noninvasive alternative routes has driven massive pharmaceutical attention. Recently, various studies of micelles strategy for noninvasive routes have been conducted to overcome the inherent barriers for uptake across the gastrointestinal tract, mucosal membranes and other in vivo noninvasive barriers, and the result argues well. The objective of this article is to summary these studies and developments of mixed micelles used on noninvasive drug delivery and provide a reference for further research.

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“…Olanzapine (OZ) is a thioeno benzodiazepine class second-generation or atypical antipsychotic that selectively binds to central dopamine D2 and serotonin (5-HT2c) receptors used for the treatment of schizophrenia and bipolar disorder [10,11]. It has poor bioavailability due to hepatic first-pass metabolism and low permeability into the brain due to efflux by P-glycoproteins.…”

Section: Introductionmentioning

confidence: 99%

Formulation and Optimization and in Vitro Characterization of Olanzapine Liposome

2021

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Objective: Olanzapine (OZ) is a thioeno benzodiazepine class second-generation or atypical antipsychotic that selectively binds to central dopamine D2 and serotonin (5-HT2c) receptors used for the treatment of schizophrenia and bipolar disorder. The present paper is aimed at developing an optimized liposome-loaded OZ as an approach for brain targeting through the nasal route for effective therapeutic management of schizophrenia. Methods: The OZ liposomes were prepared by the thin-film hydration method. Various independent variable such as phospholipid, cholesterol and sonication time was optimized by using Design-Expert® Software to obtain the dependent variables of entrapment efficiency, vesicle size and zeta potential. The optimized formulation was predicted based on the response obtained by the point prediction method. Results: The entrapment efficiency of the formulation was range between 72.9 and 85.1 %. The average particle size of all the 15 experimental runs lies between the minimum and maximum values of the size 258.33 to 325.32 nm, respectively. The zeta potential ranges from-27.53 to-11.46 mV. The optimized formulation for characterized for its morphology by Transmission Electron Microscopy (TEM). In vitro release studies of OZ-loaded liposomal formulation was carried by dialysis sac method using pH 7.4 phosphate buffer (PBS) as a medium. The maximum release was found to be 98.43±1.2 % up to 24 h. The R2 zero-order kinetics and Korsmeyer-Peppas model was found to be 0.9919 and 0.9664, respectively. The zero-order shows the best-fit model with a highest R2 value exhibiting better correlation and the ‘n’ value was also found to be 0.85; indicating both diffusion-controlled and swelling-controlled drug release that is anomalous transport. Conclusion: The results, clearly states that the prepared formulations justify the parameters and OZ might be a suitable candidate to target the brain through nasal delivery.

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Novel olanzapine analogues presenting a reduced H1 receptor affinity and retained 5HT2A/D2 binding affinity ratio

Cited by 14 publications

References 46 publications

In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

In Vivo Pharmacological Evaluations of Novel Olanzapine Analogues in Rats: A Potential New Avenue for the Treatment of Schizophrenia

Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery

Formulation and Optimization and in Vitro Characterization of Olanzapine Liposome

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