Gacyclidine; GK11

[egore]

Came across a few bits of info on this one while looking into the pharmacology of mk-801; and it seems to be significantly less neurotoxic.

IUPAC>1-[(1R,2S)-2-methyl-1-thiophen-2-ylcyclohexyl] piperidine

Heres the few bits I found>
http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"Gacyclidine is a new phencyclidine derivative with neuroprotective properties. Tritiated gacyclidine and its enantiomers bind to NMDA receptors with binding parameters similar to those of other non-competitive NMDA receptor antagonists. The (-)enantiomer, (-)GK11, exhibits an affinity (2.5 nM) similar to that of dizocilpine (MK-801), while the (+)enantiomer, (+)GK11, has a 10 times lower affinity. When its interaction with NMDA receptors is prevented, gacyclidine binds also to "non-NMDA" binding sites which are mainly located in the molecular layer of the cerebellum on the dendritic tree of Purkinje cells. These binding sites do not appear to be related to any known neurotransmitters. In primary cortical cultures, gacyclidine and its enantiomers, at 0.1 to 5.0 microM, prevent glutamate-induced neuronal death. In rats, in vivo neurotoxicity of gacyclidine is far low than that of MK-801. No necrotic neurons were detected in animals sacrificed at 18 or 96 h after treatment with gacyclidine (1, 5, 10 or 20 mg/kg i.v.). At the highest (20 mg/kg) but not the lower doses (1-100 mg/kg) electron microscopy revealed the presence of few cytoplasmic or intramitochondrial vacuoles. In soman-treated monkeys gacyclidine enhanced neuroprotective activity of "three drugs cocktail" (atropine + diazepam + pralidoxime). Moreover, in rats, gacyclidine exerts a dose- and time-dependent neuroprotection in three models of spinal cord lesion. Beneficial effects of gacyclidine include reduction of lesion size and improvement of functional parameters after injury. In traumatic brain injury models gacyclidine improves also behavioral parameters and neuronal survival. Optimal protection is obtained when gacyclidine is administered at 0 to 30 min after injury. It is, therefore, concluded that gacyclidine exhibits neuroprotective effects similar to those of other NMDA receptor antagonists, with the advantage of being substantially less neurotoxic maybe due to its interaction with "non-NMDA" binding sites."

http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"Gacyclidine, a channel blocker of N-methyl-D-aspartate receptors (NMDAR), exhibits potent neuroprotective properties and a low self-neurotoxicity. Preventing its interaction with NMDARs we demonstrate, through the use of its enantiomers, that gacyclidine also interacts with other ('non-NMDA') binding sites. The autoradiographic study showed that these sites displayed a uniform specific binding in the forebrain and a more discrete distribution in the molecular layer of the cerebellum. The 'non-NMDA' binding sites could exert a modulatory control on glutamatergic neurotransmission."

The clinical trials seem to have been discontinued after less than promising results as a neuroprotective agent>
http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"Beaufour-Ipsen is developing gacyclidine (GK-11) for the potential treatment of traumatic brain injury. Phase II clinical trials of the compound for this indication had been completed as of October 1999 and the company is looking for a partnership before undertaking further clinical development for this and, possibly, other indications [344879], [346265], [386763]. Phase II trials for acute spinal cord injury gave disappointing results and development for this indication has been discontinued [344879]."

Found a bit more on determining GK11 presence in human plasma>
http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"A modified method for the determination of gacyclidine enantiomers in human plasma by GC-MS with selected-ion monitoring using the deuterated derivative of gacyclidine (d3-gacyclidine) as internal standard was developed. Following a single-step liquid-liquid extraction with hexane, drug enantiomers were separated on a chiral fused-silica capillary column (CP-Chirasil-Dex; Chrompack). The fragment ion, m/z 266, was selected for monitoring d3-gacyclidine (retention times of 35.2 and 35.6 min for the (+)- and (-)-enantiomer, respectively) whereas the fragment ion, m/z 263, was selected for quantitation of gacyclidine (retention times of 35.4 and 35.9 min for the (+)- and (-)-enantiomer, respectively). The limit of quantitation for each enantiomer was 0.3 ng/ml, using 1 ml of sample, with a relative standard deviation (RSD) < 14% and a signal-to-noise ratio of 5. The extraction recovery of both gacyclidine enantiomers from human plasma was about 75%. The calibration curves were linear (r2 > 0.996) over the working range of 0.312 to 20 ng/ml. Within- and between-day RSD were < 9% at 5, 10 and 20 ng/ml, and < 16% at 0.312, 0.625, 1.25 and 2.5 ng/ml. Intraday and interday bias were less than 11% for both enantiomers. The chromatographic behavior of d3-gacyclidine remained satisfactory even after more than 500 injections. Applicability of this specific and stereoselective assay is demonstrated for a clinical pharmacokinetic study with racemic gacyclidine."



Anyone have better info on the human pharmacology??

 

[egore]

Turns out GK11 can be used to lessen organophosphorus nerve agents damage

http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Today, organophosphorus nerve agents are still considered as potential threats in both military or terrorism situations. These agents act as potent irreversible inhibitors of acetylcholinesterase in both central and peripheral nervous systems. Conventional treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, numerous studies have demonstrated that the excitatory amino acid glutamate also plays a prominent role in the maintenance of organophosphate-induced seizures and in the subsequent neuropathology especially through an overactivation of the N-methyl-D-aspartate (NMDA) receptor subtype. Contrary to other non-competitive NMDA antagonists successfully tested in rodents exposed to organophosphate, gacyclidine is a novel antiNMDA compound which is in the process of approval for human use in France for neurotraumatology. This review summarizes the therapeutic value of gacyclidine as a complement to the available emergency treatment against severe organophosphate poisoning. Previous data obtained from experiments on primates in several scenarios mimicking military or terrorist attacks, using soman as the nerve agent, were used. Primates pretreated with pyridostigmine and receiving conventional emergency therapy at the first signs of poisoning survive. However, only gacyclidine is able to ensure complete management of nerve agent poisoning for rapid normalization of EEG activity, clinical recovery and neuroprotection. Gacyclidine also ensures optimal management of severe nerve agent poisoning in animals neither pretreated nor receiving emergency therapy likewise during an unexpected exposure. However, this beneficial effect is obtained provided that medical intervention is conducted rapidly after intoxication. Globally, the current lack of any other NMDA receptor antagonist suitable for human use reinforces the therapeutic value of gacyclidine as a central nervous system protective agent for the treatment of OP poisoning.

http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible."

http://www.ncbi.nlm.nih.gov/pubmed/...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
"Recent experiments with primates have demonstrated that treatment with atropine/pralidoxime/diazepam, even if administered immediately after organophosphate exposure, does not totally prevent neuronal brain damage. Using primates, we have studied, for the first time, the ability of GK-11 (gacyclidine), an antiglutamatergic drug in the process of agreement for human use, given as an additional therapy, to counteract the neuropathology due to organophosphate exposure that persists after classical treatment with oxime/atropine/benzodiazepine. We have also examined the recovery of the organophosphate-intoxicated primates. Male Cynomolgus monkeys were pretreated 1 hour before poisoning with pyridostigmine, then intoxicated with 8 LD50 of soman and immediately treated with the combination pralidoxime/atropine/diazepam. Some of the animals also received GK-11 at 0.01; 0.03 or 0.1 mg/kg (i.v.) 10 minutes after soman challenge. Recovery of the primates (reflexes, movements, feeding) and the neuropathological changes that occurred three weeks after intoxication (histological examinations and neuronal cell density measurement) were compared in GK-11-treated and control animals. At all doses tested, GK-11 prevented the neuronal rarefaction of the frontoparietal cortex that was observed in soman-intoxicated animals that received only oxime/atropine/diazepam. Moreover, the 0.01 mg/kg dose of GK-11 improved the early recovery of intoxicated primates from 1 day after intoxication. In the view of the most effective management of organophosphate intoxication that is currently available, GK-11 thus appears to be a promising additional neuroprotective therapy. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication."




The more I look into this one, the more interesting it gets

 

[LuxEtVeritas]

well it is related to TCP which was a drug of abuse at one time around the 70s and 80s albeit never as prevalent as PCP, but of note a DAT-I as well as NMDA-I

i wonder if that as well has this aspect

 

[egore]

^that is one of the things I was hoping to learn more about if people had more info...

 

[Ham-milton]

this is what's being discussed if you can't picture it directly from the IUPAC

 

[Limpet_Chicken]

Does anyone else find it a little odd that they used soman in studies investigating efficacy of delayed treatment, using both GK11 and the standard oxime/atropine/diazepam treatment?

Soman denatures acetylcholinesterase very quickly, long before they administered oxime/atropine, it wouldn't have had much, if any, effect on reactivating the poisoned enxyme anyway.