Author Topic: extrapolations on the evolution of drugs  (Read 6873 times)

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zibarium

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extrapolations on the evolution of drugs
« on: March 09, 2002, 09:27:00 PM »
greetings, bees.
this is not exactly about novel routes to psychoactive compounds...its more about the route of the route to the desired compounds...hence, a bit much for the couch, where i'm cleaning the rug.


here's the premise:

the best drugs will bee active in microgram doses.
its already heading that way pretty hard; giving stupendous profits to manufacturers, and less toxicity to the consumers.

as a futurist looking backward for strategy clues, methinks the phenylethlamines are a dead end.
and more focus should bee put on some of the newer drugs that are micro-specific.

aren't the other ones all doomed to be clunkers?
aren't the cars of the great future going to bee energy producers?
if so, wouldn't looking at car design from that perspective get to the trick quicker than trying to take a little weight off a cadillac for fuel economy?

what's with oxymetazoline and related stuff that goes for sveral million bucks a pound?

computors; same deal:
nobody wishes they could have the old eniac that filled a garage; most would assume the stuff to have in the future will bee even smaller and less obtrusive.

its like one of the clues in searching for the holy grail.
its fuzzy, smells a bit randy, and is very very small

the active in s.divinorum is a wild card;
sorta new and different and highly active.


and of course, the drugs that parasitic beetles give their host ant colony so that they may be taken into the nursery to be fed ant babies and be coddled like a princess.
they say that stuff will make everyone think you're beautiful.

hest

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Re: extrapolations on the evolution of drugs
« Reply #1 on: March 09, 2002, 11:14:00 PM »
It's not a problem to make strong compound. There is amphetamins whitch are stronger than LSD.
You have to define the effect you want from the drugs, are we talkin 5-ht2a, serotonin, dopamine systems ??
Iff you want 5-ht2a there is a lot of drugs (LSD,DOB,DOM,psilocybin...)
iff you wants dopamine there is coke and amphetamin.
iff you wants serotonin(the entacnogenes) there is only xtc.
None of these drugs cost more than 1000$/kg to produce
And iff you only talk money, make some chinawhite.
Nope, we just need clean drugs, made of peaple whit some chemical skill's who doo the job right (destilation, rextalisation and so on)

Rhodium

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Re: extrapolations on the evolution of drugs
« Reply #2 on: March 09, 2002, 11:37:00 PM »
We need to modify the structures of already existing drugs, to see if it is possible to separate the desired effects from the side effects - like finding MDMA analogs without serotonergic neurotoxicity, and a wider range of stimulants - there are surprisingly few available compared to opiates and psychedelics. We also need to find more target-specific anxiolytics and antidepressants, the ones we use today in medicine are as crude as neurosurgeons with boxing gloves. And when it comes to opiates, wouldn't it be very nice to find a drug which is genuinely euphorigenic, but does not have any of the side effects commonly associated with opiates, like paralyzation of the intestines and depression of the respiratory and circulatory systems.

THAT is the future of drugs in my opinion.

zibarium

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Re: extrapolations on the evolution of drugs
« Reply #3 on: March 10, 2002, 02:34:00 AM »
agreed about that future of drugs...i'm just guessing that quantity will eventually bee one of the obvious factors; heading toward small..with a pretty wide variety of effects...stimulants; psychedelics; fentanyl...
which suggests a different haystack to sort thru...and perhaps the demise of the chem hack

hest

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Re: extrapolations on the evolution of drugs
« Reply #4 on: March 10, 2002, 03:30:00 AM »
What abouth the 'methyl' annalog of E ( with carbon instead of oxygen in the bridge) I shoudn't bee neurotox.
As fair as I remember, one of the bees was fooling around with the aldehyde, but I don't remember anny results.
 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/iap.html



Rhodium

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Re: extrapolations on the evolution of drugs
« Reply #5 on: March 10, 2002, 04:20:00 AM »
That is a good lead to the compounds of the future, as well as 5-methyl-MDA (

https://www.thevespiary.org/rhodium/Rhodium/chemistry/5-methyl-mda.html

).

The only thing left to do for these compounds is to synthesize them outside the laboratory of Dave Nichols, and bioassay them, as the rats can't tell us any details about the experience.

Adom

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Re: extrapolations on the evolution of drugs
« Reply #6 on: March 10, 2002, 09:49:00 AM »
"the demise of the chem hack"
Seems probable. Constant new restrictions on chemicals, and attempts to restrict information, will make it more difficult for new people to begin dreaming.

CrackInAmerica

hest

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Re: extrapolations on the evolution of drugs
« Reply #7 on: March 10, 2002, 12:30:00 PM »
I't might bee a bit more complicated, but with some basic skils you can produce it all from scratch, quinone,POCl3,DMF,AcOh,MeOH,Salicyl acid, aso. will newer been taken off the market.
Iff you look under precursers at Rhodium's page you can almost by it all at the mall

zibarium

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Re: extrapolations on the evolution of drugs
« Reply #8 on: March 10, 2002, 10:02:00 PM »
an implication of this implication is that the good drugs will fall into the sort of "business" that the few acid makers have...because larger quantities become small, and the chemistry skill sorta goes with it.
who wants to fuck up with a fentanyl synth?


even if its b.s., i think i like the notion of a cartel of highly qualified and dedicated chemists controling the underground, over the do-it-at-home crowd that's happening now.
as long as they aren't bought by the government.

or a crime syndicate.

El_Zorro

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Re: extrapolations on the evolution of drugs
« Reply #9 on: March 11, 2002, 04:27:00 AM »
I believe that the major drugs of abuse are directly related to the availabilty of the precursors.  The major consumers of drugs are American teens and young adults.  The major reason they consume them is the popularity of the drug.  The major factor in popularity is supply.  A very large supply of a specific drug dramitically increases it's popularity.  And the factor that allows for large amounts of a drug to be produced is the availability of precursors, and the ease of manufacture.  Coke was basically pushed from the top of society down into the slums by drug lords who had a never-ending supply.  Methamphetamine is currently taking over the country's ghettos and pushing out coke as the major drug of choice due largely to the ease of maufacture, which allows just about any idiot to make it, and the extreme availability of precursors.  Ecstacy is currently a very popular party drug, I believe because of the large, secure volume of precursor.  DMMDA is almost as, if not more powerful than MDA, but it is not a major drug of use, I believe, because there is no large, stable scorce of myristicin(sp?)  You can get it from parsley leafe oil, but not in specific amounts.  Could be 90%, could be 2%.  I believe that this is the main factor in determining major drugs of abuse, is a cost-effective precursor.

I sell crack for the CIA

hest

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Re: extrapolations on the evolution of drugs
« Reply #10 on: March 12, 2002, 01:52:00 PM »
I guess your'r right, but wath doo we want ??
I think that (meth)amphetamin has all the qualitus of a 'super coofee' drug so no more search there.
XTC has a 'potent problem' so a more active (and les toxic) entacnogen would bee nice.
LSD i a nice halucinogenic, but a bit to hard on the mind (it's hard to talk to peaple when you'r on). DOB, TMA-2, TMA-6, DOM is lighter on the mind but they are 'missing' something (might bee better with the optical pure compounds, haven done that yet).
M is not so hard for the mind, but surley have a potency problem.
Shrooms is a bit to sedative
DMT and 5-Meo-DMT is only for 'traweling' (sit back and enjoy.
I guess that my next 'search' will bee in the indole world, they look promising to mee. (I haven't forgot the super potent amphetamine, but for some reason the glass stay's in the closet)

Rhodium

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Re: extrapolations on the evolution of drugs
« Reply #11 on: March 12, 2002, 02:58:00 PM »
I find it very strange that there have been so little research in the stimulant area, that the best and strongest one we have available is methamphetamine - discovered 1887!

Greensnake

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Re: extrapolations on the evolution of drugs
« Reply #12 on: March 12, 2002, 03:23:00 PM »
Depending on what do you mean by "best and strongest one", SWIM thinks that bromantane should be reasonably good for some uses,  but it's also aparently a bit different from meth, so meth fans might not be interested in it.

Rhodium

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Re: extrapolations on the evolution of drugs
« Reply #13 on: March 12, 2002, 07:20:00 PM »
GS: Do you have any references, pharmacological/chemical data or a synthesis of that compound. A google search turned up almost nothing.

foxy2

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Re: extrapolations on the evolution of drugs
« Reply #14 on: March 12, 2002, 10:23:00 PM »
Effects of bromantan on offspring maturation and development of reflexes
Iezhitsa, I. N.; Spasov, A. A.; Bugaeva, L. I.
Neurotoxicol. Teratol.  (2001),  23(2),  213-222.

Abstract
Bromantan (N-[2-adamantil]-N-[para-bromphenyl]amine) is an "actoprotective" drug widely used in Russia as a muscle performance-enhancing agent for sportsmen and as an immunostimulator in medicine. Experiments were conducted to determine whether this compound has adverse effects on the reproduction and development of offspring. Sexually mature female rats, weighing 180¯200 g, were orally given bromantan at doses of 30 mg/kg (30-mg/kg group), 150 mg/kg (150-mg/kg group) and 600 mg/kg (600-mg/kg group) daily for 16 days, while the controls received the vehicle, amylaceous solution. Afterwards, treated females were mated with untreated males. The body weight change of the pregnant rats was monitored, as well as the length of gestation, litter size, sex ratio and number of stillborn. The offsprings were weighed and observed for external malformations, abnormalities of conditioned and unconditioned reflexes and open-field behaviour. Observation of rat dams revealed that their general state and activity in all groups did not differ significantly both during and after bromantan treatment. Bromantan had no adverse effects on body weight and gestation length of dams. Number of dams delivered per group did not differ from controls. There were stillborn rat pups in all litters, but the control group had less. One dam in the first group delivered a rat pup with a head hematoma. Litter size of the 30- and 600-mg/kg groups was decreased (by 34.9% and 44.2%, respectively) and increased in the 150-mg/kg group (by 45.1%, P<.05) in comparison with controls. Bromantan had insignificant different effects on the sex ratio of newborn in all treatment groups. Survival of pups over the first 3 months showed a loss of 40% for the 150-mg/kg group and 20% for controls. During the remaining time, death rate did not exceed 3¯6% and did not differ from those of the controls. Pups in the 30- and 600-mg/kg groups showed significantly higher weight gain during the first week (7th PND) of observation by 83.69% and 58.02%, respectively, compared to controls; subsequently, this difference in the 600-mg/kg group decreased rapidly to insignificant levels, but the 30-mg/kg group remained significantly different until PND 35 and then again at PND 77¯112. Dynamics of body weight gain of rat pups in the 150-mg/kg group during the whole (but not on PND 7) period of observation was insignificantly (on PNDs 14, 42 and 49 significantly) lower than that of the control group. Study of the functional state of rat pups' nervous system at different stages of postnatal development revealed insignificant differences in the expression of reflexes compared with those of the control group. Negative geotaxis was completed by the 8th day in controls and in treated groups earlier by an average of 1¯2 days. Surface righting was completed by the controls on the 8th day, in the 30-mg/kg group on the 6th day and in other treated groups on the 7th day. Cliff avoidance appeared a day ahead for rat pups in treated groups compared with controls. Air righting reflex in the 30- and 600-mg/kg groups was observed a day earlier than in the controls. Significant differences were observed only for two parameters (negative geotaxis and surface righting); in both cases, rat pups of the 30-mg/kg group differed from the control and 150-mg/kg groups. Early development of physical parameters was also noted, but significant differences from the control group were obtained only in the 30-mg/kg group for incisor eruption. While all pups demonstrated strength of fore and hind limbs by postnatal day 16, treated pups increased their times of maintaining their grasp (PND 15). Open-field testing (PND 40) resulted in an insignificant decrease of exploratory and locomotor behaviors for the 30-, 150- and 600-mg/kg groups. The number of grooming episodes was insignificantly decreased for the 30-mg/kg group and insignificantly increased for the 600-mg/kg group. In the passive avoidance testing, on the retention day (72 h later), entry latency for rat pups in the 30-, 150- and 600-mg/kg groups increased by 259.0%, 175.3% and 160.7%, respectively (P<.05), over their training day, while in the control group, time increased only by 1.8%.

1. Introduction
Bromantan (N-[2-adamantil]-N-[para-bromphenyl]amine) is an "actoprotective" drug [5, 16 and 29] widely used in Russia as a muscle performance-enhancing agent for sportsmen [26] and is also used as immunostimulator in medicine [13].

Actoprotectors (from Latin "aktus") was created at the Pharmacology Department of Medical Military Academy (St. Piterburgh) as a result of the search for medicines that are able to support motor activity and work capacity (mostly physical) under complicated conditions (oxygen deficiency, high environmental temperature, etc.) [5, 24, 29 and 34]. In the 1960s, research of actoprotectors under the supervision of Prof. V.M. Vinogradov was done to create drugs of unexhausting action that would surpass adaptogenes, psychostimulators and other known drugs in activity, especially under complicated conditions [5 and 34]. Bromantan is one of the first well-studied actoprotector drugs for the correction of the processes of work capacity rehabilitation both in ordinary and complicated conditions.

Bromantan was developed in the 1980s at the Institute of Pharmacology of the Russian Academy of Medical Sciences (Moscow) as a drug having psychoactivating and adaptogene properties under complicated conditions (hypoxia [18], high environmental temperature [4 and 24], physical overfatigue [18 and 24], emotional stress [16 and 18], etc.). Bromantan do not concede well-known psychostimulant of phenylalkylamine structure and its analogs (amphetamine, sydnicarb, meridil, etc.) by specific activity [16]. In contrast, bromantan has neither addictive potential nor reveals redundant and exhausting activation of sympaticoadrenergic system, or decelerates the restoring of work capacity at preventive application before forthcoming activity in complicated conditions (hypoxia, high environmental temperature, physical overfatigue, emotional stress, etc.) [16]. Bromantan has no prohypoxic activity [16].

The action of bromantan (20 and 50 mg/kg po) on spectra power EEG by Fourier in the sensorimotor cortex, dorsal hippocampus and lateral hypothalamus of the left and right rat brain hemispheres in free behavior has been investigated [13]. Bromantan leads to decreases in the total and absolute powers of all frequency bands of EEG spectra, changes structural spectra in the cortex and in hippocampus ¯¯ decreases in the relative power of theta-band and increases in the relative power of beta 1, 2-activity [13]. The basic feature of bromantan's action is a two-phase effect (its maximum occurs 2¯3 and 6¯7 h after administration), which remains up to 8 h of EEG recording. In comparison with other adamantane psychostimulants, maximum EEG changes occur at 1¯1.5 h and lasted up to 4¯5 h after administration adapromine, and maximum effect of midantan occurs at 1¯3 h and remained up to 5 h after its administration. These data suggest that bromantan has more prolonged stimulant properties than other adamantane psychostimulants [13]. Bromantan, in contrast with adapromine and midantan, has more expressed effect on biopotentials of rat brain, that is reflected both in more potent quantitative modification of EEG characteristics and changes of practically all characteristics of EEG power spectra [13].

Positive effects of bromantan on the physical efficiency are associated not only with its psychostimulating action but also with the membrane-protecting effect [17].

Bromantan is used as immunostimulator in the clinic [11] as well. Bromantan has been shown action at secondary immunodeficit condition (influencing the physical overfatigue, emotional stress, effect of toxic xenobiotics and bacterial infection). Bromantan activates humoral (is more expressed) and cellular parts of immune system [11].

Bromantan action is studied insufficiently. It is known that in formation of psychotropic and immunomodulated effects of bromantan, the important role belongs in the dopamine and serotonin systems. So, for example, amphetamine-induced stereotypies, which depend on stimulation of striatal D2-receptors, were agonized by bromantan (30 and 600 mg/kg po) [31, 32 and 35]. The data on the elimination of catalepsy by bromantan (5 mg/kg ip), caused by neuroleptics haloperidol (1 mg/kg ip) and trifluoperazine (2 mg/kg ip), indirectly confirm participation of dopamine and serotonin structures in pharmacological action of the drug [16 and 19].

Pharmacological and biochemical studies also indicate that bromantan exposure affects brain dopamine systems [12 and 19]. Bromantan (5¯50 mg/kg ip) has expressed central dopaminomimetic effect, connected to an amplification of dopamine release from presynaptic ending. Bromantan at 50¯500 mkM significantly decreased uptake of serotonin ¯¯ by isolated rats' cerebral synaptosomes and to a lesser degree inhibited uptake of dopamine [12, 16 and 19]. The central adrenergic effect of the drug is less expressed: blocking of the synaptosomal capture of norepinephrine in higher (more than 500 mkM) concentrations, and absence of an effect on the mediator content in rat brain [19].

Bromantan (50¯500 mkM) caused expressed and prolonged (registered during 8 h) increase of dopamine release [12]. Tetrodotoxin (10-6 M), perfused through microdialysis probe, partly antagonized the increase of dopamine expression caused by bromantan [12]. Extracellular levels of dopamine metabolites 3,4-dioxyphenilacetic and homovanillic acids decreased insignificantly [12 and 14].

In a number of works, the hypothesis that anxiolytic effect is present in the spectrum of pharmacological properties of bromantan is stated [25 and 26]. This is shown by per os administration of bromantan in doses of 40¯50 mg/kg, which prevents the fixed posture reaction and reduces the level of defecation in Balb/c mice in the "open-field" test and activates their behavior in the "elevated plus maze" test. It also increases the motor activity of C57Bl/c mice in both tests [25 and 26].

We hypothesize that bromantan, exerting a dopaminergic effect on activity [12, 19, 31 and 32], may probably depress prolactin secretion of lactating rats. There is sufficient evidence that the influence of dopaminomimetic drugs (i.e., bromocriptine) leads to suppression of prolactin in the blood of lactating rats on the 5th day of lactation [2, 15 and 20]. Prolactin is the main hormone of lactogenesis, and suppression of its secretion at the beginning of lactation influences milk secretion [3, 8 and 9]. It has further been shown to decrease body weight gain, thus, influencing onset of pubescence and physiological development [2 and 15]. Deficiency of this hormone also influences the mechanisms of sexual differentiation of cerebrum [3, 21, 22 and 23].

The early period of postnatal ontogenesis is the critical period in cerebral development and the quantity of hormones and neurotransmitters, as well as morphological maturation and development of the neuroendocrine system [3, 21, 22 and 23]. It has been shown that the decline in normal concentrations of neurotransmitters and hormones during this critical period may cause permanent changes of physiological functions, such as sexual behaviour, emotional state, immunity and ability to learn [2, 3, 15, 21, 22 and 23]. This early postnatal period coincides with lactation of mammals, and dam's milk is the source of hormones (i.e., prolactin) [2, 3 and 15].

Proceeding from above, we hypothesize that bromantan could affect on physical maturation of progeny. In light of this, the aim of this study was to observe the effects of the actoprotective (muscle performance enhancing) drug, bromantan, on the development of rat pups, whose


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foxy2

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Re: extrapolations on the evolution of drugs
« Reply #15 on: March 12, 2002, 10:37:00 PM »
Bromantan synthesis

In this article they make the methyl analog(methyl in place of the bromo)

Synthesis of some secondary and tertiary admantylamines by the Leuckart-Wallach reaction.    
Islam, M. Rabiul; Khan, M. A. Islam; Akhter, Nasima.   
J. Bangladesh Chem. Soc.  (1991),  4(1),  7-13.
Abstract
2-Adamantanone reacted with amines in the presence of HCO2H to give the title compds.

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slappy

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Re: extrapolations on the evolution of drugs
« Reply #16 on: March 13, 2002, 02:33:00 AM »
I have never before seen a pharmacologically active compound incorporating an Adamantane moiety.

zibarium

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Re: extrapolations on the evolution of drugs
« Reply #17 on: March 13, 2002, 05:12:00 AM »
it may bee to bold to sugest that the 'tinnier ' drugs are more apt to bee effected by the quantum effects of our expectations, etc...much like the tenderness of observing theoreticals that are no larger than the outburst of newtonian action from our very thought processess.

drugs, who's effects, could bee fine-tuned by the needs of the consumer...thru the intervention we seem to be allowed at the most subtle synaptic endings.

might this suggest why lsd is highly subjective, and set and setting sensitive?

tylenol is too bulky to cahange its structure according to our thought process whims.

PrimoPyro

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Re: extrapolations on the evolution of drugs
« Reply #18 on: March 13, 2002, 05:23:00 AM »
The lsd molecule is several times the size that of tylenol. it just takes several less lsd molecules to get an effext than it takes of tylenol molecules.

Vivent Longtemps La Ruche!

PoohBear4Ever

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Re: extrapolations on the evolution of drugs
« Reply #19 on: March 13, 2002, 05:38:00 AM »
Though activity strength is not directly related to molecular size/weight, right?

PB