Anxiolytic-like actions of anpirtoline in a mouse light-dark aversion paradigm

Metzenauer, P.; Barnes, NM; Costall, B.; Gozlan, H.; Hamon, Michel; Kelly, M.E.; Murphy, DA; Naylor, R. J.

doi:10.1097/00001756-199206000-00019

Cited by 14 publications

(4 citation statements)

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“…It was particularly noteworthy in individuals that show high levels of aggression as a result of social instigation or alcohol treatment (Fish et al .1999;de Almeida et al 2001;Rilke et al 2001). In addition, anpirtoline inhibits anxiety-like and depression-like behaviors, pain, and sexual behavior (Schlicker et al 1992;Metzenauer et al 1992;Hillegaart and Ahlenius 1998;Bouwknecht et al 2001;O'Neill and Conway 2001). The reduction in aggression was antagonized by GR127935, indicated by a rightward shift in the doseeffect curves of anpirtoline, demonstrating the 5-HT 1B receptors as the key site of action.…”

Section: Discussionmentioning

confidence: 96%

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Almeida

2002

Neuropsychopharmacology

140

104

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Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT 1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT 1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT 1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT 1Bagonists 253, zolmitriptan) The development of valid experimental protocols that model clinically relevant, excessive levels of aggressive behavior is a continuing challenge for pre-clinical research on aggression (Miczek 2001). The leading neurobiological hypothesis attributes such intense aggressive behavior, often related to expressions of impulsivity, to a deficit in brain serotonin (Linnoila et al. 1983;Virkkunen et al. 1989;Coccaro 1989). An early example of this research strategy was the demonstration that mice would exhibit intense aggressive behavior after prolonged isolated housing, and this isolation-induced aggression is associated with lower serotonin turnover in the brainstem ). Long-standing concerns with the validity and reliability of isolation-induced aggression and its limited species generality prompt the search for alternate approaches (Brain 1975;Krsiak 1975). Similarly, correlation of aggressive behavior with a single tissue or CSF measurement of serotonin or its metabolite need to be reconciled with the anti-aggressive effects of agonist NO . 2 and antagonist treatment of specific serotonin receptor subtypes (Olivier et al. 1995;de Almeida et al. 2001).The exposure of an experimental subject to a potential rival for a short time prior to the actual confrontation engenders intense levels of aggression, as originally described in mice (Lagerspetz 1969;Tellegen and Horn 1972). For example, mice, rats, and hamsters initiate attacks with very short latency and at high frequency when tested with an intruder in their home cage or in an unfamiliar locale after having been provoked previously by an opponent (Potegal 1992;Fish et al. 1999). Instigation or priming is specific for increasing aggressive behavior and does not activate locomotion, feeding, or sexual behavior (Lagerspetz and Hautojarvi 1967;Potegal and Tenbrink 1984;Potegal 1992). Even after removal of the instigating or priming stimulus, high levels of aggression persist in fish and rodents, presumably from increased "aggressive arousal" or "attack readiness" (Heiligenberg 1974;Potegal and Tenbrink 1984;Potegal 1992). At the neurochemical level, animals that have been instigated to fight are characterized by a long-lasting decrease in serotonin in hypoth...

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Section: Discussionmentioning

confidence: 96%

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Almeida

2002

Neuropsychopharmacology

140

104

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“…Anpirtoline (CHEMBL1316374) is an agonist of the 5-HT 1B , 5-HT 1A , and 5-HT 2 receptors, and an antagonist of the 5-HT 3 receptor, with K i ’s of 28, 150, 1490, and 30 nM, respectively 71,72 . However, we predicted it would bind to the nAchRs, of which it selectively bound to α3β4 at a K i of 3.41 μM and an LE of 0.536 kcal/mol/heavy atom (Figure 4d, Table S8).…”

Section: Resultsmentioning

confidence: 99%

“…Anpirtoline (CHEMBL1316374) is an agonist of the 5-HT 1B , 5-HT 1A , and 5-HT 2 receptors and an antagonist of the 5-HT 3 receptor, with K i ’s of 28, 150, 1490, and 30 nM, respectively. , However, we predicted it would bind to the nAchRs, of which it selectively bound to α3β4 at a K i of 3.41 μM and an LE of 0.536 kcal/mol/heavy atom (Figure D; SI, Table S8). In this case, the motivating SEA E3FP prediction was for the α4β2 subtype of nAchR, for which the experiment was inconclusive, suggesting either that the ligand reference data from ChEMBL distinguishing these subtypes was insufficient or that the SEA E3FP method itself did not distinguish among them, and this is a point for further study.…”

Section: Resultsmentioning

confidence: 99%

A Simple Representation of Three-Dimensional Molecular Structure

et al. 2017

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Statistical and machine learning approaches predict drug-to-target relationships from 2D small-molecule topology patterns. One might expect 3D information to improve these calculations. Here we apply the logic of the Extended Connectivity FingerPrint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the Extended Three-Dimensional FingerPrint (E3FP). By integrating E3FP with the Similarity Ensemble Approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20 and equivalent receiver operating characteristic performance. We identify classes of molecules for which E3FP is a better predictor of similarity in bioactivity than is ECFP. Finally, we report novel drug-to-target binding predictions inaccessible by 2D fingerprints and confirm three of them experimentally with ligand efficiencies from 0.442 – 0.637 kcal/mol/heavy atom.

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“…Anpirtoline (CHEMBL1316374) is an agonist of the 5-HT 1B , 5-HT 1A , and 5-HT 2 receptors, and an antagonist of the 5-HT 3 receptor, with K i 's of 28, 150, 1490, and 30 nM, respectively 68,69 .…”

Section: E3fp Predicts Correct New Drug Off-targets That Are Not Appamentioning

confidence: 99%

A simple representation of three-dimensional molecular structure

Axen

Huang

Cáceres

et al. 2017

Preprint

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Statistical and machine learning approaches predict drug-to-target relationships from 2D smallmolecule topology patterns. One might expect 3D information to improve these calculations.Here we apply the logic of the Extended Connectivity FingerPrint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the Extended ThreeDimensional FingerPrint (E3FP). By integrating E3FP with the Similarity Ensemble Approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20, and equivalent receiver operating characteristic performance. We identify classes of molecules for which E3FP is a better predictor of similarity in bioactivity than is ECFP.Finally, we report novel drug-to-target binding predictions inaccessible by 2D fingerprints and confirm three of them experimentally with ligand efficiencies from 0.442 -0.637 kcal/mol/heavy atom.

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Anxiolytic-like actions of anpirtoline in a mouse light-dark aversion paradigm

Cited by 14 publications

References 0 publications

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

A Simple Representation of Three-Dimensional Molecular Structure

A simple representation of three-dimensional molecular structure

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