3-Chloro,4-methoxyfendiline is a potent GABAB receptor potentiator in rat neocortical slices

Ong, Jennifer; Parker, David; Marino, Victor; Kerr, Donald; Puspawati, Ni Made; Prager, R. H.

doi:10.1016/j.ejphar.2004.11.029

Cited by 12 publications

(13 citation statements)

References 24 publications

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“…Thus, compound 2 acted as a positive allosteric modulator of baclofen at GABA B receptor sites under the conditions tested in these experiments. Interestingly, the inhibitory effect of this compound (19%) was similar to that reported previously for BSPP (21%) 11 and 3-chloro,4-methoxyfendiline (22%) 16 . The activity, however, was less than that observed previously on postsynaptic GABA B receptors using these alcohol analogues.…”

Section: Discussionsupporting

confidence: 88%

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors

Parker¹,

Marino²,

Sullivan³

et al. 2011

Clin Exp Pharma Physio

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1. GABA(B) autoreceptors are a subclass of GABA(B) receptors that inhibit the release of [(3) H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [(3)H]GABA, whilst the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) enhances [(3)H]GABA release in electrically-stimulated rat neocortical brain slices preloaded with [(3)H]GABA. Here, the pharmacological actions of a series of compounds derived from the positive allosteric modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), were examined on GABA(B) autoreceptors. 2. The compound, 3-(3,5-ditbutyl-4-hydroxyphenyl)-2,2-dimethyl-1-oximinopropane (compound 2), at 10 μmol/L had little effect on the stimulation-induced overflow of [(3)H]GABA when superfused alone, but when superfused in the presence of baclofen (2 μmol/L) inhibited the overflow of [(3)H]GABA. These effects were reversed by Sch 50911 (10 μmol/L). Although compounds 1-(4-chlorophenyl)-3-(4-hydroxy-3,5-diisopropylphenyl)-2-methyl-1-oximinopropane (compound 1), 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-oximinomethylcyclohexane (compound 3), 3-(3,5-ditbutyl-4-hydroxyphenyl)-1,2-diphenyl-1-oximinopropane (compound 4) and 4-(3,5-ditbutyl-4-hydroxyphenyl)-3-methyl-2-oximinobutane (compound 5) (each at 10 μmol/L) tended to reduce the stimulation-induced overflow in the presence of baclofen, an effect reversed by Sch 50911, their status as modulators is not confirmed in the present study. 3. Another derivative, 3-(3,5-ditbutyl-4-hydroxyphenyl)-1-(4-chlorophenyl)-2-methyl-1-oximinopropane (compound 6) (10 μmol/L), acted as an agonist as it inhibited the release of [(3)H]GABA by 32% (EC(50) of 3.3 μmol/L), an effect reversed by Sch 50911 (10 μmol/L). The other compounds, 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-methyl-2-oximinocyclohexane (compound 7), 4-(3,5-ditbutyl-4-hydroxyphenyl)-3,3-dimethyl-2-oximinobutane (compound 8) and 4-(4-hydroxy-3,5-diisopropylphenyl)-3,3-dimethyl-2-oximinobutane (compound 9) (each at 10 μmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABA(B) autoreceptors.

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Section: Discussionsupporting

confidence: 88%

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors

Parker¹,

Marino²,

Sullivan³

et al. 2011

Clin Exp Pharma Physio

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“…Fendiline is a GABA B R PAM (Kerr et al 2002;Ong et al 2005) and an L-type Ca 2+ channel blocker (Nawrath et al 1998;Tripathi et al 1993), and each of these may alter substrates critical for memory maintenance. While it is clear that fendiline potentiates GABA B R signaling in vitro (Chen et al 2005;Ong and Kerr 2005), there is controversy regarding the ability of fendiline to function as a GABA B R PAM in vivo (Urwyler et al 2004); therefore, the respective contribution of fendiline acting as a GABA B R PAM or as an L-type Ca 2+ channel blocker in the current study awaits further studies with selective ligands.…”

Section: Discussionmentioning

confidence: 99%

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

2013

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Rationale Fendiline is a GABAB receptor positive allosteric modulator and L-type Ca2+ channel blocker that is safe for human use. Based on these pharmacological properties, fendiline may be useful to disrupt associative memories that can drive relapse to drug use in drug-addicted individuals. Objective The current study evaluated the potential of fendiline to inhibit the maintenance and expression of learned associations between methamphetamine (meth) and an environmental context using conditioned place preference (CPP) in rats, to model for the associative learning that occurs during drug abuse by humans. Methods Following meth conditioning (1mg/kg), fendiline (5mg/kg) was administered at various post-conditioning times to ascertain if there was a temporal window during which fendiline would be effective. Results Two once-daily injections of fendiline did not influence the maintenance of CPP regardless of the post-conditioning treatment time while 10 once-daily fendiline treatments inhibited CPP maintenance (p<0.05). Fendiline administered immediately prior to the CPP test inhibited expression of meth-induced CPP in rats with a fendiline treatment history of 10 once-daily injections (p<0.05) or those that received two injections that corresponded to the last two days of the 10 day treatment (p<0.05). Fendiline did not produce preference or aversion on its own, nor did it alter motivated motor behavior. Conclusion Maintenance and expression of meth CPP is mitigated by repeated fendiline treatments when administered during the days that precede CPP testing. Reduction in the significance of meth-associated cues can reduce relapse; therefore, fendiline may be of value for addiction therapy in abstinent, meth-addicted humans.

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“…Besides amphetamine, 3,3‐diphenylpropylamine (DPPA) is the product of metabolic C‐N bond cleavage at the longer alkyl chain of the secondary amine function. In doping analysis, however, detection of neither amphetamine, nor DPPA unambiguously diagnoses an illicit prenylamine intake: both analytes could also derive from other origins, such as the therapeutic use of structurally related phenylalkylamine derivatives like fendiline …”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of urinary prenylamine metabolites by means of liquid chromatography‐tandem mass spectrometry

Beuck

Sigmund

Koch

et al. 2012

Drug Testing and Analysis

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Prenylamine is a vasodilator of phenylalkylamine structure and was used for the treatment of angina pectoris, until reports of undesirable effects including ventricular tachycardia led to a decreasing use of the drug in the 1980s. Metabolic N-dealkylation of orally ingested prenylamine can liberate amphetamine in humans and cause positive findings for amphetamine in doping and forensic analysis. In 2010, the World Anti-Doping Agency (WADA) classified prenylamine as a non-specified stimulant according to the 2010 Prohibited List, thus banning its use in sports in-competition. Supporting the development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) based detection method, a post-administration urine sample following a single oral prenylamine ingestion (Segontin(®) 60 mg) was analyzed for urinary metabolites. The LC-separated analytes were ionized in positive electrospray ionization (ESI) mode and detected as protonated ions using an AB Sciex TripleTOF 5600 quadrupole-time-of-flight hybrid mass spectrometer. Over 40 phase I metabolites were detected, including previously unknown mono- bis-, tris- and tetra-hydroxylated prenylamine, several hydroxylated and methoxylated prenylamine metabolites and (hydroxylated) diphenylpropylamine. Investigation of the collision-induced dissociation behaviours of the metabolites by high resolution/high accuracy mass spectrometry allowed for the assignment of the nature and the site of observed metabolic transformations. The most abundant phase I metabolite was confirmed as p-hydroxy-prenlyamine by chemical synthesis and stable isotope labelling of reference material. An existing routine screening assay based on direct injection and LC-MS/MS analysis of urine was modified and validated according to common guidelines, in order to allow for the detection of p-hydroxy-prenylamine in sports drug testing. The assay demonstrated the ability to detect the target metabolite at 0.1 ng/ml at intra- and inter-day imprecisions below 10%.

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3-Chloro,4-methoxyfendiline is a potent GABAB receptor potentiator in rat neocortical slices

Cited by 12 publications

References 24 publications

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Identification and characterization of urinary prenylamine metabolites by means of liquid chromatography‐tandem mass spectrometry

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3-Chloro,4-methoxyfendiline is a potent GABAB receptor potentiator in rat neocortical slices

Cited by 12 publications

References 24 publications

Pharmacological actions of oximino‐propofol analogues at GABAB autoreceptors

Pharmacological actions of oximino‐propofol analogues at GABAB autoreceptors

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Identification and characterization of urinary prenylamine metabolites by means of liquid chromatography‐tandem mass spectrometry

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Product

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About

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors

Pharmacological actions of oximino‐propofol analogues at GABA_B autoreceptors