Analogs of the dioxolanes dexoxadrol and etoxadrol as potential phencyclidine-like agents. Synthesis and structure activity relationships

Abstract

A series of dioxolane analogues based on dexoxadrol ((4S,6S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane) and etoxadrol ((2S,4S,6S)-2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane) were prepared and tested for their ability to displace [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP (1-(1-phenylcyclohexyl)piperidine) binding sites in rat brain tissue homogenates. Qualitative structure-activity relationships within this series were explored through modifications of the three major structural units of dexoxadrol, the piperidine, 1,3-dioxolane, and aromatic rings of the molecule. N-Alkyl derivatives of dexoxadrol were found to be inactive, as were those analogues where the dioxolane ring was modified. Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites. The replacement of the phenyl ring in etoxadrol by either a 2- or 3-thienyl ring led to compounds with affinity comparable to etoxadrol, and the replacement of the ethyl moiety on etoxadrol's dioxolane ring with propyl (7) or isopropyl (8) led to compounds which were more potent than etoxadrol or PCP. The most potent compound was (2S,4S,6S)-2-ethyl- 2-(1-chlorophenyl)-4-(2-piperidyl)-1,3-dioxolane (11), where a chlorine moiety was placed in the ortho position in the aromatic ring of etoxadrol. Its potency was comparable with TCP in vitro.

A Novel Method for Monitoring the Transesterification Reaction of Oil in Biodiesel Production by Estimation of Glycerol

“…Another derivative of compound 1 i.e. (4S, 6S)-4-(2-piperidyl)spiro[1,3-dioxolane-2,9 0 -[9H]-fluorene] which is an analogue of the dioxolanes dexoxadrol and etoxadrol was used as potential phencyclidine-like agent [28]. In addition, recently compound 1 was coupled with 1,2-, syn-, anti-1,3-diols and 1,3-sulfanyl alcohols to produce flexible and optically transparent molecules [in UV-visible molecules] which shows remarkable changes in the optical rotation values [29].…”

Convenient Synthesis of Building-Blocks for Pyridine/Piperidine-Decorated Crown Ethers

“…[5,12,13] The next part of our studies discloses a practical route to this compound. While trying to reproduce the method, described by Thurkauf and co-authors, [14] we have discovered some surprising features. The first one is that the target product proved to be unstable under vacuum-distillation conditions, and it underwent violent, explosion-like decomposition.…”

Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues

“…Whereas piperidines with an N-Cbz group (6,7,9,10,11) adopt the 1 C 4 -conformation due to allylic strain, the corresponding piperidines with a proton at the N-atom (8,12,13) NCbz In order to get the diastereomeric monofluoro derivatives 12a and 12c with equatorially oriented fluoro substituent, several modifications of the fluorination with DAST were investigated. In particular variation of the temperature (e.g., À100°C and À60°C) and the solvent (e.g., CH 2 Cl 2 , DMF) for the fluorination of 9b and 9d did not result in the corresponding Cbz-protected monofluoro derivatives 10a or 10c with an axially oriented fluorine atom.…”

“…In particular the substituents, the size and the heteroatoms in the oxygen heterocycle and furthermore the distance between the basic amino moiety and the oxygen heterocycle have been modified. [13][14][15] In addition to various N-substituents the piperidine ring has been exchanged for simple primary, secondary and tertiary amines. 16,17 In order to broaden the structure-affinity relationships of this class of NMDA antagonists we became interested in the influence of substituents in the piperidine moiety on the NMDA receptor affinity.…”