Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Bojarski, Andrzej J.

doi:10.2174/156802606778522186

Cited by 43 publications

(18 citation statements)

References 86 publications

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“…Moreover, other results suggest that blocking 5-HT transmission at specific 5-HT receptors may enhance or impair response inhibitory processes that are important for behavioral flexibility [18, 54]. Because 5-HT acts at seven different receptor families with multiple subtypes [5], a global increase in brain 5-HT levels may not be the optimal strategy for enhancing cognitive processes [24]. …”

Section: Introductionmentioning

confidence: 99%

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Baker

Thompson

Sweeney

et al. 2011

Behavioural Brain Research

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Recent experiments indicate that blockade of serotonin (5-HT) 2A and 2C receptors have differential effects on reversal learning. The present experiments investigated the effects of the 5-HT2A receptor antagonist, ketanserin and 5-HT2C receptor antagonist, SB242084 on acquisition and strategy-switching in a visual cue – response paradigm. Long-Evans rats were trained in a cross-maze to enter an arm based on color (visual cue version) or a specific turn response (response version). Systemic treatment with ketanserin did not affect initial learning of a visual cue or response discrimination, but ketanserin at 0.5 mg/kg significantly enhanced a switch between visual cue and response strategies. Ketanserin facilitated strategy-switching by inhibiting responses to a previously relevant strategy without affecting choices to never-reinforced strategies. Treatment with SB242084 (0.5, 1.0 or 2.0 mg/kg) did not affect acquisition of a visual cue or response discrimination. SB242084 treatment also did not affect strategy-switching. The present findings suggest that blockade of 5-HT2A, but not 5-HT2C, receptors enhance strategy switching.

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Section: Introductionmentioning

confidence: 99%

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Baker

Thompson

Sweeney

et al. 2011

Behavioural Brain Research

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“…From a chemical standpoint, the choice of FP3 and FPMP series structures was inspired by a pharmacophore model (34) and by the structure of SB269970, the prototypical 5-HT 7 antagonist (27,35). The ortho and para positions were chosen for fluorine nucleophilic substitution, and 2 hydrophobic groups were selected, leading to the synthesis of the FP3 series (4FP3 with 18 F in para, and 2FP3 with 18 F in ortho) and FPMP series (4FPMP with 18 F in para, and 2FPMP with 18 F in ortho).…”

Section: Discussionmentioning

confidence: 99%

Comparison of 4 Radiolabeled Antagonists for Serotonin 5-HT₇ Receptor Neuroimaging: Toward the First PET Radiotracer

Lemoine

Andriès²,

Bars³

et al. 2011

J Nucl Med

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Brain serotonin 7 (5-hydroxytryptamine 7, or 5-HT 7 ) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Because no radioligand has yet been successfully used to study this receptor by PET neuroimaging, the objective of the present study was to develop a 5-HT 7 18 F-labeled radiotracer. Methods: Four structural analogs of SB269970, a specific 5-HT 7 receptor antagonist, were synthesized. The nitro precursors of these analogs were radiolabeled by 18 F nucleophilic substitution. Analog antagonist effects were investigated by cellular functional assay. The cerebral distribution of radiolabeled molecules was studied by in vitro autoradiography in rats, and respective selectivity was determined by competition with the 5-HT 7 receptor antagonist SB269970 at different concentrations. Ex vivo small-animal PET studies in rats and in vivo PET studies in cats focused on the 1-(2-{(2R)-1-[(fluorophenyl)sulfonyl] pyrrolidin-2-yl}ethyl)-4-methylpiperidine (FP3) series. Results: Four analogs were synthesized from the SB269970 pharmacophore and divided into an FP3 ( 18 F-4FP3 and 18 F-2FP3) and an 1-(2-{(2R)-1-[(fluorophenyl)sulfonyl]pyrrolidin-2-yl}ethyl)-4-(2-methoxyphenyl) piperazine (FPMP) ( 18 F-2FPMP and 18 F-4FPMP) series. The chemical and radiochemical purities of the 4 radiolabeled molecules were greater than 98%. All presented suitable affinity for 5-HT 7 (apparent dissociation constant [K D ] between 1.6 and 14 nM), although the FPMP series showed moderate agonist activity for 5-HT 1A receptors. Lipophilicity values were predictive of good radiotracer blood-brain barrier penetration (logD from 1.4 to 3.9). In vitro competition with a 5-HT 7 antagonist, SB269970, revealed that only radioligands from the FP3 series were displaced by the 5-HT 7 -specific antagonist: subsequent in vivo study, therefore, focused on this series. Ex vivo 18 F-4FP3 and 18 F-2FP3 autoradiography was in accordance with the 5-HT 7 brain distribution, with few brain radioactive metabolites. PET scans in cats showed that pretreatment with a 5-HT 7 antagonist significantly reduced 18 F-2FP3 but not 18 F-4FP3 binding. Conclusion: The 4 PET radiotracers had suitable characteristics for 5-HT 7 receptor probing in vitro, although the FP3 series seemed to be more specific for in vivo imaging of 5-HT 7 receptors. In particular, on the basis of the in vivo results, 18 F-2FP3 appears to be the first PET radiotracer to enable in vivo imaging of 5-HT 7 receptors in animal models, possibly leading to neuroimaging studies in humans. Serot onin (5-hydroxytryptamine, or 5-HT) is a central neurotransmitter involved in many physiologic functions and in neurologic and psychiatric disorders. Pharmacologic studies identified numerous serotoninergic receptor families and subtypes, classified by structural, functional, and pharmacologic criteria into 7 distinct receptor classes (5-HT 1-7 ) (1).The 5-HT 7 subtype is the most recently cloned serotonin receptor (2). 5-HT 7 receptors are cou...

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“…5-HT 6 receptors were previously extensively studied for pharmacophore model development (45). The major structural feature of most 5-HT 6 For pharmacophore model building we have chosen as input structures a focused set of compounds which derived from the seed compounds of the 2D similarity selection and first round biological screening.…”

Section: Pharmacophore Screening Of Human 5-htmentioning

confidence: 99%

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories

Dobi¹,

Flachner²,

Pukáncsik³

et al. 2015

Chem Biol Drug Des

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Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed.

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Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Cited by 43 publications

References 86 publications

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Comparison of 4 Radiolabeled Antagonists for Serotonin 5-HT₇ Receptor Neuroimaging: Toward the First PET Radiotracer

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories

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Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

Cited by 43 publications

References 86 publications

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Differential effects of 5-HT2A and 5-HT2C receptor blockade on strategy-switching

Comparison of 4 Radiolabeled Antagonists for Serotonin 5-HT7 Receptor Neuroimaging: Toward the First PET Radiotracer

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT6 Antagonists from Large Commercial Repositories

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Product

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Comparison of 4 Radiolabeled Antagonists for Serotonin 5-HT₇ Receptor Neuroimaging: Toward the First PET Radiotracer

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories