dioxolane pcp analogues

[vecktor]

originally came across these as incapacitating agents in CW,

Clinical investigation of a new intravenous anesthetic--etoxadrol hydrochloride (CL-1848; U-37862A)

EL Frederickson, DE Longnecker and GW Allen

Twenty-eight patients were anesthetized with etoxadrol as primary agent. The anesthesia produced was characterized by profound analgesia and amnesia, while pharyngeal and laryngeal reflexes, as well as swallowing and lid reflexes, remained active. Systolic, diastolic, and pulse pressure were slightly increased, with associated tachycardia and tachypnea. A dose of 0.75 mg/kg produced anesthesia for an average of 26 (14 to 53) minutes. Alternating nystagmus was present for several hours and associated with dreams and/or visions that were pleasing to most patients. Six patients, however, had unpleasant dreams for up to 24 hours. One patient given an excessive dose (4.65 mg/kg) was cataleptic, amnesic, and analgesic for 6 days. The occurrence of unpleasant dreams and aberrations in over 20% of the patients suggests that the drug probably has little usefulness in anesthesia. However, the extreme safety of the drug (an LD50 equal to some 20 to 40 times the ED50) and the prolonged analgesia justified clinical testing. There was no evidence of metabolic or systemic organ system change from any of the clinical laboratory studies.

these are interesting agents based on the dioxolane skeleton. it seems that the drugs were not developed further because of the dreams post anaesthesia. Can't find any data on toxic effects.

some of the analogues in this series are more potent than pcp. A fair few years ago these were available as pcp receptor probes, are they still available now?

In reality ketamine anaogues are probably more promising, especially as there seems to be much amnesia associated with the dioxolanes.

I also wonder how one patient was given 6 times the normal dose? 6 days of anaesthesia.

MK801 is truly horrible, maybe these are nicer? from my point of view its irrelevant anyway, as I don't take dissociative anaesthetics anymore.
but I would be interested to hear of any accidental exposure of lab rats.

V

 

[Smyth]

This is the first ive heard of this group of drugs. Interesting idea with a protecting group being used in an actual drug. This is quite rare but I find this concept is intriguing.

 

[Dr.Heckyll]

Don't want to be too fussy, but these dioxadroles are not analogues of PCP chemically. Otherwise it's an interesting abstract.

 

[vecktor]

Don't want to be too fussy, but these dioxadroles are not analogues of PCP chemically. Otherwise it's an interesting abstract.

OK agreed, not strictly an analog but they act in a analogous way
I don't have access to the full article right now, but there is more on the SAR of these beasts at

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16719812&query_hl=7&itool=pubmed_docsum

I am now getting interested given the most potent versions could be synthesised from synthons representing propiophenone and a gamma amino alkane diol. the piperidine nucleus is unneccesary. I'm guessing from the abstract but the product of 1-amino- propan-2,3-diol and propiophenone could be rather potent. as would 1-amino butan-3,4-diol or its isomer.

on a side note there is a successful patent United States Patent 5556516 for separating 1-amino-propan-2,3-diol form its isomer, the patent is for distillation! how the hell can that be something non obvious and not known to someone skilled in the art. US patent office is a joke.

V


added ...

Abstract

The synthesis and NMDA receptor affinity of ring and side-chain homologues of etoxadrol and dexoxadrol are described. For the regioselective synthesis of etoxadrol homologues, the regioisomeric 4-azidobutanediols (±)-9 and (±)-14 were employed. A synthesis of the enantiomerically pure azidobutanediols (S)-, (R)-9 and (S)-, (R)-14 was developed and the homochiral building blocks were used for the synthesis of enantiomerically pure etoxadrol and dexoxadrol homologues. The affinity of the racemic and enantiomerically pure primary amines toward the phencyclidine binding site of the NMDA receptor was investigated in receptor binding studies with tritium labeled [3H]-(+)-MK-801 as radioligand. Benzaldehyde derivatives (±)-12a, (±)-13a, and (±)-16a bearing a proton at the acetalic position do not interact significantly with the NMDA receptor. An enantioselective NMDA receptor binding was observed for the trans-configured 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)ethanamine 13b, the (2-ethyl-2-phenyl-1,3-dioxan-4-yl)methanamine 16b, and the (2,2-diphenyl-1,3-dioxan-4-yl)methanamine 16c. The NMDA receptor affinity of these compounds resides almost exclusively in the (S)-configured enantiomers (2S,4S)-13b, (2S,4S)-16b, and (4S)-16c. The lowest Ki-value in this series was found for the (2S,4S)-configured 1,3-dioxolane (2S,4S)-13b (Ki = 69 nM), which is in the range of the Ki-value of the lead compounds etoxadrol and dexoxadrol, indicating that the 2-aminoethyl and the piperidin-2-yl substituents lead to similar NMDA receptor interactions.

 

[vecktor]

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http://www.sciencedirect.com/scienc...serid=10&md5=cfb98bdf6598ac4a71b851cceb620b65