Posted by chemist on August 21, 2004, at 0:15:53
In reply to Re: kp.-benzo least likely to cause cogn. impair.? » alesta, posted by Kon on August 20, 2004, at 22:37:26
> > i found an anecdote where someone states that klonopin is the only benzo that hasn't affected her memory or cognition. any thoughts?
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> This is somewhat consistent with what I've come across in the literature. Chouinard (2004)writes,
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> "The relative solubility of benzodiazepines contributes to memory impairment. The greater the lipid solubility, the greater the likelihood of memory damage...clonazepam has low lipid solubility and is least likely to cause memory impairment."
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> The lipid solubility (i.e. HPLC retention index (relative to diazepam)given in that paper are:
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> Diazepam-1.0
> Xanax-0.54
> Lorazepam-0.48
> Clonazepam 0.28
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> If this is accurate and all other things being relatively equal (?), clonazepam would seem to be one of the better benzos wrt memory while diazepam one of the worse.
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> See: J Clin Psychiatry 2004;65 (Suppl 5):7-12.
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hello there, chemist here...i admit to reading the abstract of the paper you cite above, as i do not have it on hand. before morphing into a theoretical chemical physicist, i was a chromatographer, using a Waters system with UV-Vis and conductance to determine - usually - high explosive concentrations in soils. run-of-the-mill HPLC determination of cations/anions present in groundwater was another facet, yet reverse-phase (C-18 column) was the method of choice (EPA 8330). given the aromatic or semi-aromatic character of the 1,4-benzodiazepines, and examining their structures, i am assuming that the author you cite used reveresed-phase HPLC with either uv-vis in the 310 or so nm range detection and/or fluoresence or, finally a PDA (photodiode array). relative retention times - assuming the mobile phase was lipophobic or, at the least, a 1:1 (v/v) eluent of methanol/water (18 Ohm) - are direct measurement the partitioning of the solute between the mobile phase and the stationary phase, usually silica beads (the immobile phase substrate) onto which a long chain (18-mer) aliphatic is chemisorbed. aside from functional groups and molecules of differing molecular weights affecting retention times, sometimes there is a bona-fide reaction that enhances or diminishes the mobility of the analyte. let's have a look at diazepam (DZ) and clonazepam (K). the phenyl moiety in K is substituted in the 1 position; in DZ, the phenyl group is not substituted at all. the chloro group is a weak ortho/para director for electrophilic attack (K). however, no resonance from the Cl group with the phenyl group, and thus we settle with all those electron pairs that afford hydrogen-bonding opportunities with water, to name one solvent. moving on to DZ: the six-membered ring is substituted with a chloro moiety, yet given the same opportunity to form hydrogen bonds with water, i would expect the para activation and partial conjugation at the para site to offset to a small degree the nucleophilic strength of this group: in K, the same position is occupied by a meta-director (nitro group) which deactivates the ring, thus slowing electrophilic reactions but more importantly, providing numerous electon pairs and resonance from the nitrogen and the aromatic ring. so far, the stats are somewhat comparable. the seven-membered ring is where the action is: a keto group is present in both K and DZ, and in the same position. hiwever, the neighboring nitrogen in K is a secondary amine, while the analogous nitrogen in DZ is a tertiary amine, to which a highly hydrophobic methyl group is tethered. in that nordiazepam is the active and long-lasting metabolite of DZ (K does not have a significant active metabolite) upon demethylation, it becomes more lipophilic than K, because the nitro group persists. what does all this have to do with memory and/or cognition? residence time, allosteric binding, and selectivity for certain sites within the GABA_{A} (primarily) receptor sub-type. nordiazepam has a half-life of 50-100 hours: K is 18-50 hours. in prn dosing, DZ has a quicker onset than ativan (lorazepam) because even unmetabolized parent DZ can cross the BBB faster than can lorazepam, which is more soluble due to the presence of 2 chloro groups and, more importantly, a hydroxyl moiety adjacent to a keto group in the 7-membered ring. interestingly, the action of ativan once across the BBB is sustained longer than that of DZ/NDZ, and is a bit stronger in anxiolytic action. back to memory: given that these drugs affect neurotransmitters from aspartate to GABA to glutamate to glycine and so on, it is prudent to examine not only laboratory results for solubility measures (which are typically performed in K_{ow} experiments, and are not indicative of a physiological environment that includes metabolic transformation) and retention times in a model system (isocratic flow, pure eluent, etc.) such as an HPLC or LC-MS, but the binding affinity to the receptor as well as variations on a theme that run contradictory to all the above. why is flunitrazepam (rohypnol) such a bane to society? take K, and in the phenyl group, replace Cl with F. replace the hydrogen in the secondary amine in the 7-membered ring with a methyl group (a la DZ), and now you have a date-rape drug. the active metabolite is identical to K with the only difference being the fluoro group in desmethylflunitrazepam vs. the chloro group in parent K. eventually, the 7-position nitro group (in DMFZ) is reduced to an amino group, lowering the solubility and changing the nature of the substituent from meta-directing to ortho/para directing. this last bit is not of great import, but affects binding affinity to certain sites (type I, in the case of FZ). just a late-night meandering......all the best, chemist
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