The atypical antipsychotic olanzapine is an antagonist at dopamine, serotonin and muscarinic receptor subtypes

Bymaster, F.P.; Nelson, David L.; DeLapp, Neil W.; Lucaites, Virginia L.; Wainscott, David B.; Falcone, Julie F.; Eckols, Kris; Foreman, Mark M.; Calligaro, David O.

doi:10.1016/0920-9964(96)85459-4

Cited by 5 publications

(7 citation statements)

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“…Moreover, drugs acting on receptors/ transporters highly expressed in the PFC such as antidepressant or atypical antipsychotic drugs may indirectly modulate the 5-HT and DA activity via actions on PFC targets (Bortolozzi et al 2003 ;Diaz-Mataix et al 2005). In particular, atypical antipsychotic drugs have high in-vitro affinity for 5-HT 2A receptors (Arnt & Skarsfeldt, 1998 ;Bymaster et al 1996) and produce a large occupancy of cortical 5-HT 2 receptors at therapeutic dosage (Kapur et al 1999). The present results, together with our previous observations on the presence of 5-HT 2A receptor mRNA in y55-60 % of PFC neurons projecting to the DR or VTA, suggest that atypical antipsychotic drugs may modulate the activity of DA and 5-HT neurons in a synchronous and coordinated way, an effect possibly involved in their therapeutic activity in schizophrenia and as enhancers of the antidepressant activity of SSRIs (Zhang et al 2000).…”

Section: Functional and Therapeutic Implicationsmentioning

confidence: 99%

“…Moreover, alterations of the PFC have been reported in severe psychiatric conditions such as depression and schizophrenia which are also associated with derangements of both monoaminergic systems (see for review Benes & Berretta, 2001 ;Drevets, 2001 ;Harrison, 1999 ;Lewis et al 2005 ;Manji et al 2001 ;Selemon & Goldman-Rakic, 1999). Furthermore, the functional interactions between the PFC, VTA, and DR may be crucial for understanding the therapeutic action of antidepressant and antipsychotic drugs, which target transporters or receptors expressed by DA, 5-HT and PFC neurons (Arnt & Skarsfeldt, 1998 ;Artigas et al 1996 ;Bymaster et al 1996 ;Cortés et al 1988 ;Mengod et al 1989 ;Santana et al 2004Santana et al , 2009Weiner et al 1991). In particular, recent findings indicate the presence of 5-HT 2A receptor mRNA in a large proportion of PFC neurons projecting to the DR or VTA (Vázquez-Borsetti et al 2008), which suggests that atypical antipsychotic drugs may partly exert their therapeutic effect by attenuating the activity of excitatory inputs to these midbrain nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei

Vazquez

Celada

Cortés

et al. 2010

Int. J. Neuropsychopharm.

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Derangements of the prefrontal cortex (PFC) and of brainstem monoaminergic systems occur in depression and schizophrenia. Anatomical and functional evidence supports a PFC control of the brainstem monoaminergic systems. Similarly, the PFC contains a high density of monoamine receptors for which antipsychotic drugs exhibit high affinity. This raises the possibility that pathological or drug-induced changes in PFC may subsequently alter monoaminergic activity. Recent data indicate that a substantial proportion of PFC pyramidal neurons projecting to the ventral tegmental area (VTA) or the dorsal raphe nucleus (DR) express the 5-HT 2A receptor mRNA, which suggests that atypical antipsychotic drugs affect serotonergic and dopaminergic function by targeting PFC 5-HT 2A receptors. Using electrophysiological and tract-tracing techniques we examined whether PFC pyramidal neurons projecting to DR are segregated from those projecting to the VTA. Sequential electrical stimulation of these nuclei in anaesthetized rats evoked antidromic potentials from both areas in the same pyramidal neurons of the medial PFC (60 %, n=30). A similar percentage of dual DR+VTA projection neurons (50 %) was obtained using the reciprocal collision test (n=85). Similarly, tracer application (Fluoro-Gold in VTA and cholera toxin B in DR, or vice versa) retrogradely labelled pyramidal neurons in PFC projecting to VTA (81¡18), to DR (52¡9) and to both nuclei (31¡4, n=5 rats). Overall, these results indicate that the PFC may simultaneously coordinate the activity of dopaminergic and serotonergic systems within a short temporal domain, supporting a concerted modulation of the ascending serotonergic and dopaminergic activity during antipsychotic drug treatment.

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Section: Functional and Therapeutic Implicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei

Vazquez

Celada

Cortés

et al. 2010

Int. J. Neuropsychopharm.

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“…The antipsychotic drug olanzapine, used in the treatment of schizophrenia [generic name Zyprexa; see: http://pi.lilly.com/ us/zyprexa-pi.pdf], was deemed suitable for this purpose because (1) it is not found in the NCI 2D structure repository, thereby representing an out-of-sample data point for prediction, and (2) it is known to promiscuously bind a number of different G protein-coupled receptors with nanomolar affinity. 66 The rationale followed here was that if high-binding affinity between olanzapine and a number of oGPCRs was predicted by the trained SVM, confidence in the generalization potential of the model would increase.…”

Section: Cross-target Analysis Of High-affinity Ligandsmentioning

confidence: 99%

“…The results of the method on this out-of-sample data point are therefore consistent with documented findings of cross-target affinity of this compound for GPCRs. 66 For reference, the two-dimensional structure of olanzapine is presented in Figure 1. 6 and 7, which present the highest-scoring ligands for oGPCRs produced by the virtual screen.…”

Section: Cross-target Analysis Of High-affinity Ligandsmentioning

confidence: 99%

Virtual Screen for Ligands of Orphan G Protein-Coupled Receptors

Bock

Gough²

2005

J. Chem. Inf. Model.

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This paper describes a virtual screening methodology that generates a ranked list of high-binding small molecule ligands for orphan G protein-coupled receptors (oGPCRs), circumventing the requirement for receptor three-dimensional structure determination. Features representing the receptor are based only on physicochemical properties of primary amino acid sequence, and ligand features use the two-dimensional atomic connection topology and atomic properties. An experimental screen comprised nearly 2 million hypothetical oGPCR-ligand complexes, from which it was observed that the top 1.96% predicted affinity scores corresponded to "highly active" ligands against orphan receptors. Results representing predicted high-scoring novel ligands for many oGPCRs are presented here. Validation of the method was carried out in several ways: (1) A random permutation of the structure-activity relationship of the training data was carried out; by comparing test statistic values of the randomized and nonshuffled data, we conclude that the value obtained with nonshuffled data is unlikely to have been encountered by chance. (2) Biological activities linked to the compounds with high cross-target binding affinity were analyzed using computed log-odds from a structure-based program. This information was correlated with literature citations where GPCR-related pathways or processes were linked to the bioactivity in question. (3) Anecdotal, out-of-sample predictions for nicotinic targets and known ligands were performed, with good accuracy in the low-to-high "active" binding range. (4) An out-of-sample consistency check using the commercial antipsychotic drug olanzapine produced "active" to "highly-active" predicted affinities for all oGPCRs in our study, an observation that is consistent with documented findings of cross-target affinity of this compound for many different GPCRs. It is suggested that this virtual screening approach may be used in support of the functional characterization of oGPCRs by identifying potential cognate ligands. Ultimately, this approach may have implications for pharmaceutical therapies to modulate the activity of faulty or disease-related cellular signaling pathways. In addition to application to cell surface receptors, this approach is a generalized strategy for discovery of small molecules that may bind intracellular enzymes and involve protein-protein interactions.

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“…In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11)(12)(13)(14)(15)(16). These motifs have been referred to as ''privileged structures'' (11).…”

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confidence: 99%

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Bisson

Cheltsov

Bruey-Sédano

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico ''drug repurposing'' procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.androgen receptor ͉ drug design ͉ prostate cancer C urrent approaches for discovery of novel chemical leads against a molecular target rely heavily on high-throughput screening (HTS) and to a lesser extent on virtual ligand screening (VLS) techniques. HTS has provided rapid lead identification for numerous drug targets (1-8); however, HTS also has major drawbacks, including a significant level of false positives and false negatives and low hit rates for many targets (9). Successful leads from HTS can also suffer from poor bioavailability and unwanted toxicity profiles of compounds. These problems result partially from the nature of the chemical libraries used for HTS. Furthermore, because the pharmacological properties of most compound libraries are largely unknown, there is an additional high risk that optimization of hits identified with HTS will not be sufficient for their evolution into real drugs.In contrast, retrospective analysis of marketed drugs reveals that their physicochemical and structural properties are clustered around preferred values and scaffolds (10). In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11-16). These motifs have been referred to as ''privileged structures'' (11). These observations lead to an assumption that the chemical space of potential drugs is limited. Consequently, currently marketed...

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The atypical antipsychotic olanzapine is an antagonist at dopamine, serotonin and muscarinic receptor subtypes

Cited by 5 publications

References 0 publications

Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei

Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei

Virtual Screen for Ligands of Orphan G Protein-Coupled Receptors

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

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