Author Topic: Phamacologic characteristics of a loperamide derivative (Read 243 times)

solidstone · « **on:** October 26, 2010, 12:24:12 AM »

In response to: dehalogenation of loperamide with uv light and isopropanol - Enkidu

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do you think getting rid of the chlorine is going to make the structure more active? I can't but help of the loperamide analog Diphenoxylate. It has no chlorine and its still garbage. What exactly are you trying to get at through the de-halogenation?

jon · « **Reply #1 on:** October 26, 2010, 12:38:29 AM »

it's already been verified by numerous chemists that esterification with propionic anhydride yields a narcotic on par with heroin.
have a look at the morphine rule.
the benzene ring can have different electronic characteristics to it activating it increases it's binding to the mu receptor deactivating it as in the case of para halogenation decreases it's affintiy for that pocket of the mu-receptor
and diphenoxylate follows the SAR's of the demerol type analgesics the ester is straight RC=OOR
reversing the ester ROC=OR increases it's potency considerably.
diphenoxylate's active constituent is actually not even an ester but an acid.

Enkidu · « **Reply #2 on:** October 26, 2010, 12:50:01 AM »

hxxp://dx.doi.org/10.1067%2Fmcp.2000.109156

Quote from: solidstone on October 26, 2010, 12:24:12 AM

do you think getting rid of the chlorine is going to make the structure more active? I can't but help of the loperamide analog Diphenoxylate. It has no chlorine and its still garbage. What exactly are you trying to get at through the de-halogenation?

Diphenoxylate and loperamide are close enough, structurally, to be assumed to be ligands at the same receptor. However, even small structural differences can significantly modulate efficacy. A "small" change can even change an agonist to antagonist. Smaller changes, still, can alter second messenger signaling. Since the ethyl carboxylate moiety of diphenoxylate is a bioisostere for an aromatic moiety in many receptor systems, you can think of a phenyl group in it's place. As you can see, the structures are quite different.

Of course, if the p-glycoprotein inhibited bioassays hadn't been moderately promising, this assay would be low on the to-do list.

Enkidu · « **Reply #3 on:** October 26, 2010, 01:25:46 AM »

Quote from: jon on October 26, 2010, 12:38:29 AM

it's already been verified by numerous chemists that esterification with propionic anhydride yields a narcotic on par with heroin.

Does the esterification abolish affinity to the p-glycoprotein pump? That's something I've wondered about.

Quote from: jon on October 26, 2010, 12:38:29 AM

the benzene ring can have different electronic characteristics to it activating it increases it's binding to the mu receptor deactivating it as in the case of para halogenation decreases it's affintiy for that pocket of the mu-receptor
and diphenoxylate follows the SAR's of the demerol type analgesics the ester is straight RC=OOR
reversing the ester ROC=OR increases it's potency considerably.
diphenoxylate's active constituent is actually not even an ester but an acid.

I think that the bulk of the halogen interferes with the binding pocket. IIRC, only fluorine strongly affects the electronic characteristics of the phenyl moiety, but chlorine, as the second most electronegative halogen, may have some slight effect.

Potency is not everything. There are plenty of potent DAT inhibitors that have no value from a recreational perspective. As for GPCRs, agonist directed, second messenger signaling must also be accounted for in addition to pharmokinetics. Additionally, most of the ridiculously potent opioids just cause severe respiratory depression, without an accompanying recreational value. It will be interesting to see whether that's the case here.

jon · « **Reply #4 on:** October 26, 2010, 04:18:55 AM »

it falls into the prodine class and, those compounds give good euphoria.
i would'nt be suprized if aryl dehalogenation enhanced it's qualities as well.
esterification just completes the puzzle if you will to the morhine rule.
the carbonyl oxygen replacing the 4,5 epoxy bridge and the three carbon tail the cylohexene ring making it structurally more resemblant of morphine.

Enkidu · « **Reply #5 on:** October 26, 2010, 05:23:26 PM »

Well, diphenoxylate also has the prodine/pethidine substructure, but it doesn't produce any euphoria. The structures of prodine and dehalogenated loperamide are too different to make any deductions about receptor responses.

My question about the esterified derivative of loperamide was in relation to the p-glycoprotein pump. The reason that loperamide isn't active centrally active is that it gets thrown out of the brain back into the blood by the transporter. So, some people (you) have noted euphoria upon administration of the esterified derivative. So, either 1) the esterfication prevents the ligand from recognizing the p-glycoprotein transporter or 2) the pharmokinetic properties of the ligand (such as lipophilicity) have increased to the point that the transporter can be overwhelmed and you can achieve a high enough concentration of the drug in the brain. I'm going with number two, but I want your thoughts.

Also, I don't think that loperamide follows the morphine rules, due to 1 & 4 (the N,N-dimethylamido moiety, therefore, doesn't satisfy #1). Does #1 simply require an alkyl spacer between the tertiary nitrogen and bulkier substituents?

1. A tertiary nitrogen with a small alkyl substituent.
2. A quaternary carbon.
3. A phenyl group or its isosteric equivalent directly attached to the quaternary carbon.
4. A 2 carbon spacer between the quaternary carbon and the tertiary nitrogen.

Increased drug delivery to the brain by P-glycoprotein inhibition
Abu J. M. Sadeque, Christoph Wandel, Hauibing He, Selina Shah and Alastair J. J. Wood
Clinical Pharmacology & Therapeutics 68, 231-237 (September 2000)
doi:10.1067/mcp.2000.109156

Quote

Background: Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate–dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression.

Results: Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). [....]

Conclusion: [...] the lack of respiratory depression produced by loperamide [...] can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.

jon · « **Reply #6 on:** October 26, 2010, 05:39:57 PM »

thanks for that one, you are a scientific goldmine; i'm starting to see the light glory be!!!

aside from the shenaigans i'll tell you why dehalogenation at the p-chloro position markedly enhances mu receptor affinity.
if you look at the structure activity relationships of des-methylprodine (of which the ester of this compound is one of) you will find that a methyl group at the 4 position of the benzene ring decreases the potency of prodines substantially.

***From information so far available, it appears that the 4-aryl substituent of prodine-type compounds must be a phenyl group if optimum activity is to be attained. In the case of alphaprodine, Randall and Lehman ([14] ) have reported substitution of 4-phenyl by 4-cyclohexyl to result in a considerable fall in activity (see compound 5, table 2), while work in our own laboratories ([30] ) has shown that replacement by p-tolyl, o-tolyl and m-tolyl gives progressively less active substances (see compounds 25, 18 and 22, table 2).****

naturally table two isn't there...

the reference provided for the m,o,and p tolyl derivatives of prodine is:

BECKETT, CASY, KIRK & WALKER, J. Pharm. Pharmacol ., 1957, 9, 939

i have a paper just attached it look at table IV the p-tolyl-desmethyl-4-phenylpiperidine-4-ol is .15% the potency of morphine wheras the desmethylprodine is between .5 and equipotent to morphine.
but it is'nt the referenced article.

reference:

http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1957-01-01_4_page006.html

Enkidu · « **Reply #7 on:** October 26, 2010, 09:36:44 PM »

Synthesis and characterization of meperidine analogs at the P-glycoprotein efflux transporter
by Mercer, Susan L., Ph.D., University of Maryland, Baltimore, 2008, 195 pages; AAT 3337301

Enkidu · « **Reply #8 on:** October 26, 2010, 10:52:04 PM »

The opioid in question is #34.

Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides
Stokbroekx, Raymond A.; Vandenberk, Jan; Van Heertum, Albert H. M. T.; Van Laar, Gerard M. L. W.; Van der Aa, Marcel J. M. C.; Van Bever, Willem F. M.; Janssen, Paul A. J.
Journal of Medicinal Chemistry (1973), 16(7), 782-6

Quote

4-(P-chlorophenyl)-4-hydroxy-N,N-dimethyl-?,?-diphenyl-1-piperidinobutyramide-HCl (loperamide) (I-HCl) [34552-83-5] and 4-(4-chloro-?,?,?-trifluoro-m-tolyl)-4-hydroxy-N,N-dimethyl-?,?-diphenyl-1-piperidinobutyramide-HCl (fluperamide) [34552-82-4] were approx. twice as potent as diphenoxylate in protecting rats from diarrhea induced by castor oil, and had a considerably better relative constipating specificity. To synthesize I, 2,2-diphenyl-4-hydroxybutyric acid ?-lactone was reacted with HBr to yield 4-bromo-2,2-diphenylbutyric acid [37742-98-6], which reacted with SOCl2 and NHMe2 to yield dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide [37743-18-3], then with 4-(p-chlorophenyl)-4-piperidinol [39512-49-7] to form I.

jon · « **Reply #9 on:** October 28, 2010, 09:08:30 PM »

enkidu regarding your question about the morphine rule #1
tertiary nitrogen with a small alkyl substituent

this rule is'nt written in stone you will notice that phenyl ethyl morphine is 20X stronger than morphine itself.

Enkidu · « **Reply #10 on:** July 07, 2011, 03:40:30 AM »

Quote

Interestingly, loperamide, a peripherally restricted MOR agonists that is used as
an over-the-counter treatment for diarrhea (immodium), differs from morphine in
that it promotes robust MOR- b -arrestin interactions and induces MOR internalization
in HEK cells (unpublished observations: L.M.B.). When administered to mice,
loperamide delays gastrointestinal transit; however, loperamide has no inhibitory
effect on transit times in mice lacking b -arrestin2 (65). These observations underscore
that the functional selectivity of agonists observed in cell culture may not
always translate into functional selectivity in vivo as the two agonists promote different
MOR regulatory profiles in regard to b -arrestin-mediated events in cells yet
b -arrestin2 appears to be equally important for mediating the effects of both drugs
in gut. The regulation of MOR in respect to opioid-induced constipation may prove
to be a valuable therapeutic target (67– 68) .

65 . Raehal KM , Walker JK , Bohn LM . Morphine side effects in beta-arrestin2 knockout mice .
J Pharmacol Exp Ther 2005 ; 314 (3) : 1195 – 201 .
66 . Bohn LM , Raehal KM . Opioid receptor signaling: relevance for gastrointestinal therapy . Curr
Opin Pharmacol 2006 ; 6 (6) : 559 – 63 .
67 . Bruns IR , Chhum S , Dinh AT , et al . A potential novel strategy to separate therapeutic- and sideeffects
that are mediated via the same receptor: beta-arrestin2/G-protein coupling antagonists .
J Clin Pharm Ther 2006 ; 31 (2) : 119 – 28 .
68 . Ross GR , Gabra BH , Dewey WL , Akbarali HI . Morphine tolerance in the mouse ileum and
colon . J Pharmacol Exp Ther 2008 ; 372 : 561 – 72 .
69 . Berg KA , Maayani S , Goldfarb J , Scaramellini C , Leff

Enkidu · « **Reply #11 on:** September 18, 2011, 04:21:54 AM »

The opiate in question has an LD50 (half the animals dosed die) of 2.5mg/kg in mice and 2.0mg/kg in rats. Normalizing to skin surface area, the equivalent human dose is .020mg/kg and .040mg/kg, respectively. That means, for a 70kg human, a "dose" of between 14 and 28mg has a good chance of killing.

MICHAEL WOSTER and ALBERT HERZ
Opiate Agonist Action of Antidiarrheal Agents in vitro and in vivo - Findings in Support for Selective Action
Naunyn-Schmiedeberg's Arch. Pharmacol. 301,187-194 (1978)

hypnos · « **Reply #12 on:** September 20, 2011, 02:14:19 PM »

Hey enkidu, you Know, you have my complete respect, as a chemist and scientist, so I dont feel I'm in a position to question your data, but sometimes words or the manner of explanation, Varies significantly enough from country to country,state to state...although I had a look around, I"m no quite sure how this is "worked out", and even though I searched I wasnt coming up with numbers like yours, In fact I wasnt coming up with much!!
Could you possibly give a lite version,maybe some Empirical formula I am unaware of, or other type of explanation of the way they make this determination/bioassay

Quote

Normalizing to skin surface area, the equivalent human dose is .020mg/kg and .040mg/kg, respectively. That means, for a 70kg human, a "dose" of between 14 and 28mg has a good chance of killing.

I just cant seem to find with TSE "How" they make this pharmacokinetic study and comparison

Thanx buzzer

Hyppy

Enkidu · « **Reply #13 on:** September 20, 2011, 05:47:09 PM »

http://127.0.0.1/talk/index.php/topic,2583.msg26066.html#msg26066

Author Topic: Phamacologic characteristics of a loperamide derivative (Read 243 times)

solidstone

Phamacologic characteristics of a loperamide derivative

jon

Phamacologistic characteristics of a loperamide derivative

Enkidu

Phamacologic characteristics of a loperamide derivative

Enkidu

Phamacologic characteristics of a loperamide derivative

jon

Re: Phamacologic characteristics of a loperamide derivative

Enkidu

Re: Phamacologic characteristics of a loperamide derivative

jon

Re: dehalogenation of loperamide with uv light and isopropanol

Enkidu

Re: Phamacologic characteristics of a loperamide derivative

Enkidu

Re: Phamacologic characteristics of a loperamide derivative

jon

Re: Phamacologic characteristics of a loperamide derivative

Enkidu

Re: loperamide is it possible to form a grignard complex of???

Enkidu

Re: Phamacologic characteristics of a loperamide derivative

hypnos

Re: Phamacologic characteristics of a loperamide derivative

Enkidu

Re: Phamacologic characteristics of a loperamide derivative