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Propofol and Analogues?

Ham-milton

Ham-milton

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Does anyone know if any propofol analogues have similar activity? I'd be interested in them if they didn't have the steep dose-response curve propofol does, but I can't find anything about them.

Well, let me qualify that a bit. There's substantial info about propofol analogues that are stronger, but not weaker ones.

No one (smart) would want to abuse a depressant as potent as benzodiazepines, and has death risks of barbs.

I think something ultra-potent, high-respiratory depression producing depressants are a really bad idea. A good depressant can still kill, but it should be active around 100mg, I think. Are any propofol analogues like that?
 
4D-QSAR Analysis of a Set of Propofol Analogues: Mapping Binding Sites for an Anesthetic Phenol on the GABAA Receptor

Matthew D. Krasowski, Xuan Hong, A. J. Hopfinger, and Neil L. Harrison*

Department of Anesthesia and Critical Care, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, Illinois 60637, Laboratory of Molecular Modeling and Design, M/C-781, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, and C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, A-1050, Weill Medical College of Cornell University, New York City, New York 10021

Received October 4, 2001

Abstract:

A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the -aminobutyric acid type A (GABAA) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand-receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand -OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABAA receptor; it follows that the GABAA receptor is therefore the likely site of propofol's anesthetic action.
 
J. Med. Chem., 41 (11), 1846 -1854, 1998. jm970681h S0022-2623(97)00681-X
Web Release Date: April 28, 1998
Copyright © 1998 American Chemical Society

Propofol Analogues. Synthesis, Relationships between Structure and Affinity at GABAA Receptor in Rat Brain, and Differential Electrophysiological Profile at Recombinant Human GABAA Receptors

Giuseppe Trapani,* Andrea Latrofa, Massimo Franco, Cosimo Altomare, Enrico Sanna, Marcello Usala, Giovanni Biggio, and Gaetano Liso

Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy, and Dipartimento di Biologia Sperimentale, Sezione di Neuroscienze, Università di Cagliari, Via Palabanda 12, 09123 Cagliari, Italy

Received October 7, 1997

Abstract:

A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABAA receptors determined by the inhibition of the specific [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to rat whole brain membranes. Introduction of halogen (Cl, Br, and I) and benzoyl substituents in the para position of the phenyl group resulted in ligands with higher potency at inhibiting [35S]TBPS binding. A quantitative structure-affinity relationship (QSAR) study demonstrated that affinity is enhanced by increases in lipophilicity of the ligand whereas affinity is adversely affected by increases in size of the substituent para to the phenolic hydroxyl group. Consistent with the displacement of [35S]TBPS and with the activation of GABAA receptors, we demonstrate that ligands displaying high affinity (i.e., 2-4, and 8) are able to increase GABA-stimulated chloride currents in oocytes expressing human GABAA receptors and to directly activate chloride currents in an electrophysiological assay. Among them, compound 4 showed a rather peculiar profile in the electrophysiological examination with cloned 122 GABAA receptors. Indeed, compared to propofol, it displayed a much greater efficacy at potentiating GABA-elicited chloride currents, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to compound 4 pharmacological properties that are more similar to anxiolytic and anticonvulsant drugs than to those of general anesthetics.
 
I wonder what class of drug 4-OH(or possibly 4-MeO)-2,6-diisopropylamphetamine would fall under or whether it would be active at all?

All in all, though, my propofol experiences while under anesthesia were very favorable.
 
I can't find the full paper, but judging from the way they describe it, yeah, probably.

I doubt the diisopropyl amphetamine would retain any activity.
 
Hey Ham-milton, I got those two papers - i'm interested in these too. You know where...
 
Propofol is supposed to also have Cannibinoid (CB1)agonist activity which are said to add to it's effect. Does any1 have more info on this. Could there be a propofol analog that's mainly a Cannibinoid? Could it be potentiated with a FAAH inhibitor?

Also, seeing as how propofol painfullness is related to the fact that it's an oil. Could it be smoked? To convert it to something water soluble can an acid like HCl be added to it?
 
I went under anaesthesia recently, using propofol/fentanyl, and although it stung slightly, it wasn't what I could class as proper pain, more of a tingling, and not actually unpleasant.

Coming out of it, now that really did feel good, apart from the shivering it caused.

Propofol doesn't have a basic nitrogen, or a charged group, so nope, no salts here, its 2,6-diisopropylphenol.

Look up fospropofol on wikipedia, they created a water soluable derivative with some more favourable pharmokinetics for abuse, notably a slower onset time and no need for a lipid delivery vehicle.

Perhaps administration of it as a phenoxide, although I'm not sure as that won't come undone immediately in biological conditions (I am really quite wrecked at the moment:P) am I barking up the wrong tree here?
 
I've been most interested in 4-IP for a long time, ever since I saw it discussed in a paper on propofol analogues. It was described as have activity quite similiar to benzos, not barbs (which pro more closely resembles).

This isn't a great study, I admit, and the write up couldn't be shorter, I don't think, but it's definitely interesting; I'd prefer to see a binding assay, see if it actually has any BZD receptor affinity.

What it's really missing is if it causes DA release :)

TITLE: EFFECTS OF PROPOFOL AND 4-IODO- PROPOFOL ON SPONTANEOUS RELEASE OF GLUTAMATE AND NOREPINEPHRINE FROM RAT CORTICAL SYNAPTOSOMES

AUTHORS: Hugh C. Hemmings Jr, MD, PhD, Ratnakumari Lingamaneni, PhD, Victor N. Pashkov, PhD
AFFILIATION: Weill Medical college of Cornell University, New York, NY.

INTRODUCTION: In order to relate the structure-activity relationships of propofol (PRO; 2,6-diisopropylphenol), several derivatives have been synthesized.1 Among them, 4- iodopropofol (4-IP) significantly differed from PRO in its actions. Unlike PRO, which induces sedation and loss of righting reflex in rats, 4-IP had no behavioural effects.2 The effects of PRO and 4-IP on spontaneous release of endogenous glutamate (GLU) and [3H]norepinephrine (NE) from synaptosomes were compared in the present study.
METHODS: 4-IP was synthesized1 and purified by HPLC. Synaptosomes (SYN; pinched off nerve terminals) were isolated from adult male Sprague-Dawley rats using Percoll gradients as approved by IACUC. GLU release was measured using enzyme- coupled fluorimetry. [3H]NE release was analyzed by super- fusion of preloaded SYN with buffer containing pargyline and L- ascorbic acid to inhibit NE metabolism. DMSO (final 0.1%), used as vehicle for PRO and 4-IP, did not have signficant effects.
RESULTS:

GLU release (% of control; mean±SD; n-4-6

PRO*


4-IP#

14 mM 123±57


30 mM 154±25

28 mM 143±24


60 mM 225±43 (p<0.05)

[3H]NE release (% of control; mean±SD; n=4)

PRO*


4-IP#

16 mM 125±10


25 mM 554±52 (p<0.05)

32 mM 147±5 (p<0.05)


50 mM 665±69 (p<0.05)

*free concentration, # nominal concentration; free concen-tration ~50% less. Statistical differences between control and experi- mental values were determined by analysis of variance with the Fisher post hoc test.

The increases in GLU and [3H]NE release by both PRO and 4-IP were tetrodotoxin (1 mM)-insensitive and Ca2+-independent.
CONCLUSIONS: 4-IP induced basal GLU and [3H]NE release more potently than PRO. These distinct effects on neurotrans- mitter release may contribute to their different behavioural effects in rats.
REFERENCES:

1J Med Chem 1998, 41:1846;

2Br J Pharmacol 1999, 126:1444. Supported by NIH grant GM 58055.
Click to expand...
 
Seems odd, actually; they make it sound like it's an important property- but at the doses used, no way.
 
I will share a secret with you [edited]

Not only does it seemingly cure most illnesses and pain, but it also makes me feel great. Mind you, it is required in large amounts. There is a west-asian/mid-eastern herb that produces black seeds full of []. The seeds are ground and mixed with honey to make a black paste. This is then eaten as quickly as possible to preserve the [] content. The first time I had it I actually experienced a sort of "rush" - my whole body became tingly, and my mind became tranquil and clear.

If I'm not mistaken, Propofol was actually made from [].

I've seen more than one journal articles that describe [] as gabaergic in the same manner as propofol.

In all honesty, I have reason to believe that this is the Soma of the vedas.


EDIT: Substance name removed for safety reasons.
 
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Jamshyd: thanks for sharing this info. What is the name of the herb. Have you had any further experiences with thymol-content seeds since this first time?
 
So if one where to obtaine {mystery substance X} in it's pure crystal form, on average how much would need to be ingested to get the effect u descibed Jamshyd?
 
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Damn, big secret hugh? Y all the Hush hush? I'll help keep yer secret, but I still wanna know the effective dose;)
 
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