Gabapentin-like drugs (in nature?)

[panic_the_digital]

Seems like there should be SOMETHING comparable in nature. My recollection of their structures is that they are very simple.

 

[MurphyClox]

There's hardly anybody referencing Jamshyd's original question, I can't believe it. Why?? I request in particular ControlDenied to just stay quite, as he seems absolutely incompetent to provide any substantial response to this question.

As I feel Mr. Jamshyd really deserves an answer, I surveyed the literature today. This might be of interest:

"(L)-Phenylglycine, but not necessarily other α2δ subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats."
Pain 2006, 125(1-2), p.136-142

Abstract
Gabapentin and pregabalin have been demonstrated, both in animal pain models and clin., to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the α2δ subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacol. approach to test the hypothesis whether high affinity interactions with the α2δ subunit alone could lead to attenuation of neuropathic pain in rats. The anti-allodynic effects of gabapentin and pregabalin, along with three other compds. - (L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA) - discovered to be potent α2δ ligands, were tested in the rat spinal nerve ligation model of neuropathic pain. Gabapentin (Ki = 120 nM), pregabalin (180 nM) and (L)-phenylglycine (180 nM) were shown to be anti-allodynic, with resp. ED50 values of 230, 90 and 80 µmol/kg (p.o.). (L)-Phenylglycine was as potent as pregabalin and equi-efficacious in reversing mech. allodynia. In contrast, two ligands with comparable or superior α2δ binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 .mu.mol/kg (p.o.), although these compds. achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent α2δ subunit ligands do not. These results suggest that addnl. mechanisms, besides α2δ interactions, may contribute to the effects of compds. like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.

I hope that helps a bit. Apparently, (L)-PheGly is a damn simple compound and should be avaible. Dunno about metabolic stability though, but my guess would be that it gets degraded quite fast. What a pity...

- Murphy

 

[MurphyClox]

It is eye-catching that there are several dozen of publications dealing with the presumably similar action of gabapentin/pregabalin, but hardly anything that deals with other compounds that share the mechanism of action of the former ones. Not surprisingly, otherwise Jamshyd wouldn't have asked this

Anyway, I found at least one publication that deals with 'novel' compounds, applying the bioisotery concept. These should be metabolically more stable that the peptides from my last posts. See this:

"Oxadiazolone bioisosteres of pregabalin and gabapentin."
Bioorganic & Medicinal Chemistry Letters 2009, 19(1), p.247-250

Abstract
A series of oxadiazolone bioisosteres of pregabalin and gabapentin were prepd., and several were found to exhibit similar potency for the α2δ subunit of voltage-gated calcium channels. Oxadiazolone I derived from gabapentin achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance assocd. with I was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.

How to prepare those compounds, well, is the concern of other forums.

- Murphy

 

[MurphyClox]

I strongly recommend the following as a reading on the topic:

"Pharmacology and mechanism of action of pregabalin: The calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery "
Epilepsy Research 2007, 73, p.137

Summary
Pregabalin (Lyrica™) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2–delta (α2–δ) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to α2–δ subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to α2–δ subunits, including structure-activity analyses of compounds binding to α2–δ subunits and pharmacology in mice deficient in binding at the α2–δ Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.

14 pages, incl. over 3 pages of references. Very useful article on that topic!

- Murphy

 

[Jamshyd]

Wow, thanks Murph, you're the man!

This is the kind of response I've been hoping for when I started this thread. Definitely a good place to start.

Thanks a lot for posting. I'll definitely give these a thorough read and see what I can come up.

I'd appreciate it if mods can clean up some of the garbage earlier in this thread, and as a fellow mod, suggest try their hand at the infraction system .

 

[MurphyClox]

You're absolutely welcome mate!

 

[Tsukasa]

Would anyone have a list of the neurotransmitters that pregab reduces the synaptic release of? I'd imagine glutamate is one of them.

 

[ollieideal]

I want to know of these law suits surrounding gabapentin, I use it for nerve damge pain, and pain that can be derived from my brain, (so thought)but yeah i would like to know, what synaptic release it prohibits, and if i can mimick these with potentiators that are natural or homeopathic, but i doubt it.
I really rate gabapentin . After 12 yrs of banging up, lastly a good 4-5 yrs in my legs I damaged the valves that pump the blood from the ankles and heels up the legs which in turn blocks veins etc and courses swelling in the legs and in turn nerve damge from swelling etc, the gabapentin since taking it, well, iv'e not had another episode of swelling, I dont use and havent used for a yr now (needles that is). The problems that required gabapentin, funnily only started after i gave up needles

 

[125loons]

I want to know of these law suits surrounding gabapentin, I use it for nerve damge pain, and pain that can be derived from my brain, (so thought)but yeah i would like to know, what synaptic release it prohibits, and if i can mimick these with potentiators that are natural or homeopathic, but i doubt it.
I really rate gabapentin . After 12 yrs of banging up, lastly a good 4-5 yrs in my legs I damaged the valves that pump the blood from the ankles and heels up the legs which in turn blocks veins etc and courses swelling in the legs and in turn nerve damge from swelling etc, the gabapentin since taking it, well, iv'e not had another episode of swelling, I dont use and havent used for a yr now (needles that is). The problems that required gabapentin, funnily only started after i gave up needles

Olliedeal, I tried to reply to your PM, but I can't send it due to not being a Bluelighter yet. How many posts is that?

 

[nuke]

Go to Other Drugs please if you guys wanna talk about getting high on Gabapentin... This thread is about gabapentin-like drugs which are natural and if you guys aren't on topic anymore I'll delete your posts.

 

[protoject]

Hey Jamshyd, Sorry everyone I know this is an old thread but I had the same question as Jamshyd, and i ACCIDENTALLY found out that Rhynchophylline from cat's claw is also a calcium channel blocker, I haven't done my research yet to see if this is really doing anything much similar to gabapentin which also acts as a calcium channel blocker with chronic use, about to do my research now though.

 

[protoject]

oh also just found another chemical with possible similarity. KAVAIN from kava kava, except it is not only a calcium channel blocker but also is a sodium channel blocker.

 

[sekio]

This thread is 4 years old....

you're not contributing a lot here either. anyone can look on wikipedia for Ca channel blockers. open a new thread if you have something productive to say