Bidirectional allosteric modulation of strychnine-sensitive glycine receptors by tropeines and 5-HT3 serotonin receptor ligands

Maksay, Gábor

doi:10.1016/s0028-3908(98)00127-0

Cited by 31 publications

(41 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…High concentrations of strychnine are believed to antagonize also GABA A receptors and to interact with alpha 7 nAChRs (Hussy et al, 1997;Maksay, 1998;Palma et al, 1999;Shirasaki et al, 1991;Xu, 1999) and inhibition of GABA A (for review see Korpi, 1994) or accumbal nAChRs (Nadal et al, 1998) decreases EtOH intake. However, in this study strychnine per se did not affect EtOH intake, which would argue against interference with these receptor populations in the dose applied.…”

Section: Discussionmentioning

confidence: 99%

Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake‐Reducing Effect of Acamprosate

Chau

Hoifodt-Lido

Löf

et al. 2009

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background:We have previously demonstrated that strychnine-sensitive glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area are involved in mediating ethanol (EtOH)-induced elevation of dopamine in the rat mesolimbic dopamine system. This neuronal circuitry was also demonstrated to mediate dopamine elevation in the nAc after both taurine, an endogenous agonist of GlyRs, and acamprosate, a synthetic derivate of homotaurine. The aim of this study was to investigate whether the EtOH intake-reducing effect of acamprosate involves accumbal GlyRs.Methods: For this purpose, we used a voluntary EtOH consumption model where EtOH medium-and high-preferring rats were implanted with guide cannulae in the nAc. The animals received daily injections of acamprosate or 0.9% NaCl before accessing a bottle of 6% EtOH and a bottle of water. After 2 days, a microinjection of strychnine or vehicle preceded the daily systemic injection and bottle-access period.Results: Acamprosate, but not saline, decreased EtOH intake. Pretreatment with Ringer in the nAc did not influence EtOH intake in saline or acamprosate-treated animals. Pretreatment with strychnine had no effect on EtOH intake in saline-treated animals, whereas it completely reversed the EtOH intake-reducing effect of acamprosate.Conclusions: Based on current and previous results, we suggest that acamprosate primarily interacts with accumbal GlyRs and secondarily with ventral tegmental nAChRs, in a similar manner to that previously observed with EtOH and taurine. The interaction between acamprosate and GlyRs does not only influence dopamine output in the nAc but also EtOH consumption, giving further support for our hypothesis that GlyRs are of importance in EtOH reinforcement.

show abstract

Section: Discussionmentioning

confidence: 99%

Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake‐Reducing Effect of Acamprosate

Chau

Hoifodt-Lido

Löf

et al. 2009

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…Although many GlyR modulators have been discovered through recent discovery programs, receptor specificity remains a serious issue, arguably due to a heavy focus on the discovery of GlyR modulators from known nonspecific modulators 48,65 . While strategically quick to deliver GlyR modulators, the approach seems predestined to fail on delivering the requisite selectivity 48,54 .…”

Section: Antagonistsmentioning

confidence: 99%

“…While strategically quick to deliver GlyR modulators, the approach seems predestined to fail on delivering the requisite selectivity 48,54 . This situation and the current high demand for novel, potent and specific GlyR modulators 1 clearly warrant a new approach to discover GlyR modulators.…”

Section: Antagonistsmentioning

confidence: 99%

“…Of the allosteric modulators, tropisetron (1.5), zatosetron (1.7) and bemesetron (1.8) are considered the best because of their potent modulating activity, displacing GlyRs with nanomolar potency 48,49 , and high bioavailability against GlyRs 1 . Similarly, strychnine represents the best example of GlyR antagonist 1 as this alkaloid is the prototypic competitive antagonist of GlyRs showing nanomolar Ki values at recombinant and native receptors in binding and functional assays 2 .…”

Section: Glyr Modulatorsmentioning

confidence: 99%

“…The lack of specificity is even shown by strychnine, which remains the only known pharmacological probe for GlyRs 1 . These facts show the urgent need and value in discovering specific GlyR modulators that can serve as either pharmacological probes and/or drugs for treating various CNS diseases mediated by GlyRs.Although many GlyR modulators have been discovered through recent discovery programs, receptor specificity remains a serious issue, arguably due to a heavy focus on the discovery of GlyR modulators from known nonspecific modulators 48,65 . While strategically quick to deliver GlyR modulators, the approach seems predestined to fail on delivering the requisite selectivity 48,54 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Discovery of Novel, Potent and Selective Glycine Receptor Modulators from Southern Australian Sponges

Balansa¹

View full text Add to dashboard Cite

Consisting of five subunits (!1-!4 and "), glycine receptors (GlyRs) orchestrate inhibitory neurotransmission in the central nervous system (CNS). Mutation and/or dysfunction of different GlyR subunits are associated with CNS diseases such as spasticity and movement disorders (GlyR!1), hyperekplexia (GlyR !1, GlyR!2 and GlyR"), epilepsy (GlyR!2 and GlyR!3) and inflammatory pain (GlyR!1 and GlyR!3). In particular, GlyR!3 has recently emerged as the target of choice for the treatment of chronic inflammatory pain due to its discrete distribution at the lamina II dorsal horn spinal cord, the pain terminal. Unfortunately, while known GlyR modulators lack specificity for GlyRs, that render them undrugable, little is known about GlyR modulators from marine natural products (MNPs), despite the important roles of MNPs in drug discovery programs.Together with the biomedical potential of MNPs and the unmet medical needs in treatment of CNS diseases, recent advances in spectroscopic and ion channel technologies strongly suggest the importance of MNPs in the discovery of novel, potent and specific GlyR modulators.Consequently, chapter 1 discusses the various potential medical benefits of GlyRs and/or MNPs in the search for a cure for CNS diseases, with emphasis on chronic inflammatory pain. They include:• Structural diversity and pharmacological aspect of GlyRs;• Possible uses of GlyR modulators in therapy;• The importance of advanced technologies in discovering anti-inflammatory pain drugs from marine resource;• MNPs as a prolific source of bioactive molecules; and• The role of MNPs in the discovery of new pain relief drugs.Chapter 2 prioritizes marine extracts as our first step in identifying MNPs as potential GlyR modulators. Taking advantage of the yellow fluorescence protein (YFP) assay, we screened nBuOH extracts of >2,500 Australian and Antarctic marine invertebrates against GlyR!1, GlyR!2 and GlyR!3 and compared the images for control and tested extracts. This screening yielded 27 active extracts (3 strong, 19 moderate and 5 weak antagonist extracts). Along with this screening, liquid chromatography mass spectrometry (LCMS) analysis established 7 priority specimens described in the following three chapters. and (7E,12Z,20Z,18S)-variabilin (3.53) compounds from three Irciniidae sponges. The isomers 3.51 and 3.52 were successfully isolated and assigned as a single pure compound without derivatisation.Importantly, by means of liquid chromatography-solid phase extraction nuclear magnetic resonance (LC-SPE-NMR), we managed to isolate and elucidate the structure of minor metabolites (3.45-3.50). were unique in that they all featured an unusual functionality, a glycinyl lactam and in case of ircinialactam D, a dihydroxy diacid moiety. Using automated patch clamp electrophysiology (APCE), we evaluated 3.45-3.53 against !1 and !3 GlyRs and identified 3.46 and 3.47 as strong and specific GlyR!1 potentiators with EC 50 values of 1.0 µM and 0.5 µM respectively and 3.53 as a potent and selective GlyR!3 antagonist (IC 50 ...

show abstract

The Inhibitory Glycine Receptor—Simple Views of a Complicated Channel

Breitinger

Becker

2002

ChemBioChem

View full text Add to dashboard Cite

Bidirectional allosteric modulation of strychnine-sensitive glycine receptors by tropeines and 5-HT3 serotonin receptor ligands

Cited by 31 publications

References 23 publications

Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake‐Reducing Effect of Acamprosate

Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake‐Reducing Effect of Acamprosate

Discovery of Novel, Potent and Selective Glycine Receptor Modulators from Southern Australian Sponges

The Inhibitory Glycine Receptor—Simple Views of a Complicated Channel

Contact Info

Product

Resources

About