LuxEtVeritas
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F-Phenibut and α2δ subunit VDCC : Rationale for meaningful activity at this site?
Looking for research supportive that F-Phenibut/FluoroPhenibut, a derivative wherein the Chloro group of Baclofen is subbed for a Fluoro, has a pharmacological action that produces a balanced activity at α2δ subunit-containing voltage-gated calcium channels and GABA-B. As well, it is claimed to have the propensity to develop less tolerance to GABA-B more similarly to Baclofen, which this would seem to be more of a logical deductive extrapolation perhaps.
Baclofen is known to have only very modest affinity α2δ subunit, certainly compared to its activation of GABA-B. Phenibut itself is now postulated via supportive research to produce a fairly balanced activity, though it is solely the R-isomer that entails this action (references below). I see no rationale why the Fluoro substitution would create such a shift in affinities at the two receptors, other than perhaps it is somewhat closer given that it appears to have less affinity/efficacy at GABA-B than baclofen itself, perhaps 10-20% of such seems a viable estimation. However, there is no correlative rationale for why the substitution would NOT diminish the activity seen with Phenibut at α2δ subunit that it would at this level of diminished GABA-B activation skew the receptor activity profiles to be 'balanced'.
Thus, more balanced perhaps, but perhaps not significantly so to be significantly therapeutically relevant, given that as I am aware baclofen is very weak at α2δ subunit. This is bearing that Baclofen is in the range of 100-fold more potent by weight as an agonist of the GABA-B receptor in comparison to Phenibut, and in accordance, is used at far lower relative dosages. As such, the actions of Baclofen on α2δ subunit-containing VDCCs are likely not clinically-relevant; thusly, by extrapolations to what is given with F-Phenibut, such is neither likely clinically-relevant at this subunit.
Zvejniece, Liga; Vavers, Edijs; Svalbe, Baiba; Veinberg, Grigory; Rizhanova, Kristina; Liepins, Vilnis; Kalvinsh, Ivars; Dambrova, Maija (2015). "R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology Biochemistry and Behavior. 137: 23–29. doi:10.1016/j.pbb.2015.07.014. ISSN 0091-3057. PMID 26234470.
Vavers, Edijs; Zvejniece, Liga; Svalbe, Baiba; Volska, Kristine; Makarova, Elina; Liepinsh, Edgars; Rizhanova, Kristina; Liepins, Vilnis; Dambrova, Maija (2015). "The neuroprotective effects of R-phenibut after focal cerebral ischemia". Pharmacological Research. doi:10.1016/j.phrs.2015.11.013. ISSN 1043-6618.
On a related note, if anyway cares to give an informed rationale as to what dialkylation (and like conjugations) would create within such additions to the amine and hydroxyl of all these compounds please fire away.
Lastly, if anyone has reference to the intrinsic activity of common agents at both sites I'd be highly appreciative.
TIA
Looking for research supportive that F-Phenibut/FluoroPhenibut, a derivative wherein the Chloro group of Baclofen is subbed for a Fluoro, has a pharmacological action that produces a balanced activity at α2δ subunit-containing voltage-gated calcium channels and GABA-B. As well, it is claimed to have the propensity to develop less tolerance to GABA-B more similarly to Baclofen, which this would seem to be more of a logical deductive extrapolation perhaps.
Baclofen is known to have only very modest affinity α2δ subunit, certainly compared to its activation of GABA-B. Phenibut itself is now postulated via supportive research to produce a fairly balanced activity, though it is solely the R-isomer that entails this action (references below). I see no rationale why the Fluoro substitution would create such a shift in affinities at the two receptors, other than perhaps it is somewhat closer given that it appears to have less affinity/efficacy at GABA-B than baclofen itself, perhaps 10-20% of such seems a viable estimation. However, there is no correlative rationale for why the substitution would NOT diminish the activity seen with Phenibut at α2δ subunit that it would at this level of diminished GABA-B activation skew the receptor activity profiles to be 'balanced'.
Thus, more balanced perhaps, but perhaps not significantly so to be significantly therapeutically relevant, given that as I am aware baclofen is very weak at α2δ subunit. This is bearing that Baclofen is in the range of 100-fold more potent by weight as an agonist of the GABA-B receptor in comparison to Phenibut, and in accordance, is used at far lower relative dosages. As such, the actions of Baclofen on α2δ subunit-containing VDCCs are likely not clinically-relevant; thusly, by extrapolations to what is given with F-Phenibut, such is neither likely clinically-relevant at this subunit.
Zvejniece, Liga; Vavers, Edijs; Svalbe, Baiba; Veinberg, Grigory; Rizhanova, Kristina; Liepins, Vilnis; Kalvinsh, Ivars; Dambrova, Maija (2015). "R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology Biochemistry and Behavior. 137: 23–29. doi:10.1016/j.pbb.2015.07.014. ISSN 0091-3057. PMID 26234470.
Vavers, Edijs; Zvejniece, Liga; Svalbe, Baiba; Volska, Kristine; Makarova, Elina; Liepinsh, Edgars; Rizhanova, Kristina; Liepins, Vilnis; Dambrova, Maija (2015). "The neuroprotective effects of R-phenibut after focal cerebral ischemia". Pharmacological Research. doi:10.1016/j.phrs.2015.11.013. ISSN 1043-6618.
On a related note, if anyway cares to give an informed rationale as to what dialkylation (and like conjugations) would create within such additions to the amine and hydroxyl of all these compounds please fire away.
Lastly, if anyone has reference to the intrinsic activity of common agents at both sites I'd be highly appreciative.
TIA
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- either that or we're left with Paflobut perhaps 8
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