(S)-N-tert-Butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors

Cliffe, Ian A.; Brightwell, Christopher I.; Fletcher, Allan; Forster, Elaine A.; Mansell, Howard L.; Reilly, Yvonne; Routledge, Carol; White, A. C.

doi:10.1021/jm00062a028

Cited by 84 publications

(35 citation statements)

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“…22 The peculiar relationship between α 2 -AR activation and 5-HT function, highlighted by such studies, might justify the dose-dependent U-shaped trend exhibited by the anti-immobility effect of our α 2C -AR/5-HT 1A -R agonists. To support our observations, experiments in the presence of the 5-HT 1A -R antagonist WAY 100135 24 and the α 2 -AR antagonist yohimbine 25 were carried out. Both antagonists, ineffective when given alone, significantly and similarly contrasted the actions evoked by 0.025 mg/kg dose of (S)-(+)-1, (R)-(−)-2, and (S)-(+)-2 ( Figure 4).…”

Section: (S)-(+)-and (R)-(−)-2-(2-cyclopropylmethyl)propionic Acid Mesupporting

confidence: 58%

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Bello

Diamanti

Giannella

et al. 2012

ACS Med. Chem. Lett.

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This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α 2C -adrenoreceptor (AR) agonism/α 2A -AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT 1A receptor (5-HT 1A -R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α 2C -AR agonists/α 2A -AR antagonists/5-HT 1A -R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction. KEYWORDS: α 2 -adrenergic ligands, 5-HT 1A -R agonists, morphine withdrawal symptoms reduction, antidepressant-like effect M orphine use is the classical approach in the treatment of chronic or cancer-related pain. Nevertheless, even when legally allowed and closely monitored, long-term opioid administration alters central pain-related systems, inducing tolerance and dependence. Opioid addiction, termed a "chronic relapsing disease", is associated with a myriad of health and social problems; hence, its management is an extremely important area of research. 1 α 2 -Adrenoreceptors (α 2 -ARs), which have been demonstrated to be extremely sensitive to opioid exposure and to play a key role in opiate withdrawal symptoms, 2 belong to the superfamily of G-protein-coupled receptors. The three α 2A -, α 2B -, and α 2C -AR subtypes are widely distributed in the central nervous system (CNS) and peripheral tissues. 3 Studies with genetically engineered mice have demonstrated that the α 2A subtype mediates hypotension, sedation, and analgesia, as well as inhibition of monoamine release and metabolism in the brain. The α 2B subtype mediates vasoconstriction, while the α 2C subtype appears to be involved in many CNS processes, such as the startle reflex, stress responses, and control of locomotion as well as feedback inhibition of adrenal cathecolamine release. Moreover, in the brain, α 2A -and α 2C -ARs, as "heteroreceptors", inhibit dopamine and serotonin release. Finally, the α 2C subtype can contribute to adrenergic-opioid synergy and spinal α 2 -agonist-mediated analgesia. 3−5 In detoxification, α 2 -AR agonists such as clonidine and lofexidine are often clinically used alone or in combination with traditional treatments to reduce the intensity of withdrawal symptoms, thus increasing treatment duration. However, the α 2A -AR activation triggered by these compounds is responsible for side effects such as sedation and hypotension.

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Section: (S)-(+)-and (R)-(−)-2-(2-cyclopropylmethyl)propionic Acid Mesupporting

confidence: 58%

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Bello

Diamanti

Giannella

et al. 2012

ACS Med. Chem. Lett.

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“…The notion that stimulation of Na',K+-ATPase activity is accomplished by activation of the 5-HTlA receptor subtype is further supported by the fact that the effect of 8-OH-DPAT is abolished in a concentration-dependent manner by the specific 5-HTIA receptor antagonist, (+)-WAY 100135. This compound is the first silent 5-HTlA receptor antagonist for which a considerable degree of specificity has been demonstrated (Cliffe et al, 1993). Therefore, despite the failure of immunohistochemical techniques to detect the presence of 5-HTIA receptors in the proximal nephron, the present data provide functional evidence for their presence in this nephron segment.…”

Section: Statisticsmentioning

confidence: 57%

Antagonistic actions of renal dopamine and 5‐ hydroxytryptamine: increase in Na⁺, K⁺‐ATPase activity in renal proximal tubules via activation of 5‐HT_1A receptors

Soares‐da‐Silva¹,

Pinto-do-Ó²,

Bertorello³

1996

British J Pharmacology

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1 5-Hydroxytryptamine (5-HT) is antinatriuretic. Since this effect-of 5-HT is not accomplished by changes in glomerular haemodynamics, we have examined in this study whether 5-HT may influence sodium excretion by affecting the Na+, K+-ATPase activity in renal cortical tubules. 2 Na+, K+-ATPase activity was determined as the rate of [32P]-ATP hydrolysis in renal cortical tubules in suspension. Basal Na+,K+-ATPase activity in renal tubules was 4.8+0.4 imol Pi mg-' protein h-' (n = 8). The 5-HTA receptor agonist, (±)-8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT) (10 to 3000 nM) induced a concentration-dependent increase (P <0.05) the stimulatory effect of 8-OH-DPAT. The stimulatory effect of 8-OH-DPAT was found to be timedependent (15 + 2% and 66 + 7% increase at 2.5 and 5.0 min, respectively). The 5-HT2 receptor agonist a-methyl-5-HT (100 to 3000 nM) did not induce any significant changes in Na+,K+-ATPase activity (5.0 + 1.5 ymol Pi mg'-protein h-i; n = 4).3 The stimulatory effect 8-OH-DPAT was absent when homogenates were used. Stimulation occurred at a Vm,, concentration (70 mM) of sodium supporting the notion that stimulation occurs independently of increasing sodium permeability. 4 The inhibitory effect of dopamine (P<0.05) on Na+,K+-ATPase activity was blunted by coincubation with 8-OH-DPAT (0.5 jM).5 It is concluded that activation of 5-HTIA receptors increases Na+,K+-ATPase activity in renal cortical tubules; this effect may represent an important cellular mechanism, at the tubule level, responsible for the antinatriuretic effect of 5-HT.

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“…Only until very recently, no full 5-HT 1A receptor antagonists were available for these studies. The identification of (S)WAY 100135 and WAY 100635 as full 5-HT 1A receptor antagonists (Cliffe et al, 1993;Critchley et al, 1994;Fletcher et al, 1993a,b) prompted the intensive investigation of other potential full 5-HT 1A receptor antagonists. PET studies of [O-methyl-11 C]WAY 100635 in humans revealed that the distribution of radioactivity was highly localized and consistent with the known distribution of 5-HT 1A receptors .…”

Section: Resultsmentioning

confidence: 99%

“…BMY7378 appears to exhibit these same partial agonist properties (Greuel and Glaser, 1992). (S) WAY 100135, an arylpiperazine analog, appears to be a very highly selective and potent 5-HT 1A receptor antagonist at both the presynaptic (somatodendritic) and postsynaptic 5-HT 1A receptor sites (Cliffe et al, 1993;Critchley et al, 1994;Fletcher et al, 1993a,b). The IC 50 of (S) WAY 100135 is 15 nM in rat hippocampal membrane preparations.…”

Section: Introductionmentioning

confidence: 95%

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p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

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The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

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(S)-N-tert-Butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors

Cited by 84 publications

References 0 publications

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Antagonistic actions of renal dopamine and 5‐ hydroxytryptamine: increase in Na⁺, K⁺‐ATPase activity in renal proximal tubules via activation of 5‐HT_1A receptors

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

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(S)-N-tert-Butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors

Cited by 84 publications

References 0 publications

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

Antagonistic actions of renal dopamine and 5‐ hydroxytryptamine: increase in Na+, K+‐ATPase activity in renal proximal tubules via activation of 5‐HT1A receptors

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

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About

Antagonistic actions of renal dopamine and 5‐ hydroxytryptamine: increase in Na⁺, K⁺‐ATPase activity in renal proximal tubules via activation of 5‐HT_1A receptors