PASS Prediction

[Hammilton]

http://195.178.207.233/PASS/predict.php

I'm wondering if someone could help explain how this works. I entered N,N-diethyl-3-phenylcyclohexanamine, a structure I drew looking for non-analogue's that'd fit with with cocaine / dimethocaine's pharmacophore (focusing on the phenyl and amine placement). When I noticed that I finally got my username and password to use PASS while cleaning out 37 pages of emails (that with netscape required clicking on every single one!) I thought to plug it in. I've posted the top results below (in order from most likely to least likely, but none getting below 50% and though I cut it off pretty early because everything I was interested in was already included.

Now, what I'm trying to understand is this: how exactly does it reach these conclusions? I mean, I concluded this already, but I compared it in 3D to known DAT ligands. The site has an explanation of the math but I don't really understand it. I assume that to conclude this it'd have to calculate configuration in a 3D array and then compare that to arrays available for a variety of ligands. It must also compare in 2D as well, right? That's why it'd suggest that it was a sigma agonist, I would think.

These were the top results:

27 Substructure descriptors; 0 new.
41 Possible activities at Pa > 50%
Pa Pi for Activity:
0,889 0,007 Psychosexual dysfunction treatment
0,876 0,007 Cardiovascular analeptic
0,814 0,016 CC chemokine 2 receptor antagonist
0,778 0,007 Antiparkinsonian
0,811 0,064 Fibrinogen receptor antagonist
0,759 0,027 Dopamine D4 agonist
0,714 0,006 Peptidoglycan glycosyltransferase inhibitor
0,691 0,005 Dopamine agonist
0,694 0,014 Antidepressant
0,712 0,061 Cardioprotectant
0,681 0,040 Antineurotic
0,704 0,068 Urologic disorders treatment
0,636 0,004 Melatonin 1 antagonist
0,643 0,025 Membrane permeability inhibitor
0,623 0,034 Neurotransmitter uptake inhibitor
0,640 0,051 Antineurotoxic
0,603 0,028 Psychotropic
0,600 0,038 Tocolytic
0,603 0,058 Torsades de pointes
0,564 0,020 Prostaglandin H2 antagonist
0,561 0,018 Prostaglandin E1 antagonist
0,572 0,042 Dependence treatment
0,532 0,007 5 Hydroxytryptamine 1A agonist
0,622 0,100 2-Haloacid dehalogenase (configuration-inverting) inhibitor
0,596 0,078 CYP2D16 substrate
0,597 0,081 Arrhythmogenic
0,510 0,008 5 Hydroxytryptamine agonist
0,527 0,025 Cyclic AMP agonist
0,528 0,032 Vasodilator, renal
0,540 0,047 Calmodulin antagonist
0,508 0,019 Analeptic
0,538 0,058 Antidiarrheal
0,507 0,032 Anxiolytic
0,502 0,032 Corticotropin releasing factor antagonist
0,503 0,033 Sigma receptor agonist

It also provides an "effects" probability which I don't entirely understand, but these are listed:
EFFECTS
0,644 0,025 Antitoxic
0,640 0,051 Antineurotoxic
0,644 0,025 Hepatoprotectant
0,644 0,025 Membrane permeability inhibitor
0,544 0,008 Anorexiant
0,544 0,008 5 Hydroxytryptamine agonist
0,942 0,005 Cardiotonic
0,527 0,025 Antiarrhythmic
0,527 0,025 Cyclic AMP agonist
0,942 0,005 Dopamine agonist
0,527 0,025 Cyclic AMP agonist
0,644 0,025 Antiinflammatory
0,644 0,025 Membrane permeability inhibitor
0,527 0,025 Antineoplastic
0,527 0,025 Cyclic AMP agonist
0,603 0,058 Arrhythmogenic
0,603 0,058 Torsades de pointes
0,644 0,025 Neuroprotector
0,644 0,025 Membrane permeability inhibitor
0,561 0,136 Nerve growth factor agonist
0,547 0,047 Calmodulin antagonist
0,942 0,005 Antiparkinsonian
0,942 0,005 Dopamine agonist
0,623 0,034 Neurotransmitter uptake inhibitor
0,561 0,136 Nerve growth factor agonist
0,942 0,005 Psychostimulant
0,942 0,005 Dopamine agonist

Just for reference, these are the results cocaine itself gives:

37 Substructure descriptors; 0 new.
27 Possible activities at Pa > 50%
Pa Pi for Activity:
0,911 0,004 Dependence treatment
0,906 0,007 QT interval prolongation
0,901 0,007 Convulsant
0,887 0,007 Cardiotoxic
0,876 0,006 CYP2A substrate
0,858 0,003 CYP2A5 substrate
0,827 0,006 Anesthetic
0,821 0,006 Anesthetic local
0,781 0,014 Psychosexual dysfunction treatment
0,785 0,037 Beta-adrenergic-receptor kinase inhibitor
0,729 0,004 Mydriatic
0,715 0,003 Cocain dependency treatment
0,696 0,008 Antiparkinsonian
0,654 0,020 CYP3A substrate
0,618 0,018 Spasmolytic
0,601 0,007 Narcotic
0,611 0,018 Antisecretoric
0,590 0,001 Dopamine transporter antagonist
0,587 0,005 Dopamine uptake inhibitor
0,554 0,008 5 Hydroxytryptamine antagonist
0,545 0,010 Cholinergic antagonist
0,544 0,015 CYP2B substrate
0,517 0,006 Hypertensive, ophthalmic
0,513 0,007 CYP2B2 substrate
0,529 0,035 CYP3A4 substrate
0,506 0,014 Acetylcholine antagonist
0,518 0,042 Analgesic

I love that cocaine dependency treatment and just dependence treatment (the latter being the top result!) are listed.

 

[dread]

That's neat. Would you mind checking the results for n-methyl-2-phenylcyclohexanamine?

 

[Hammilton]

Nothing surprising about it

25 Substructure descriptors; 0 new.
28 Possible activities at Pa > 50%
Pa Pi for Activity:
0,812 0,013 Antineurotic
0,739 0,026 Arrhythmogenic
0,720 0,019 Torsades de pointes
0,712 0,012 Membrane permeability inhibitor
0,710 0,012 Antidiarrheal
0,693 0,007 Antiviral (Influenza)
0,712 0,040 Dopamine D4 agonist
0,666 0,008 Sleep disorders treatment
0,670 0,015 Antidepressant
0,672 0,022 Antidyskinetic
0,660 0,025 Neurotransmitter uptake inhibitor
0,635 0,008 Vasodilator, renal
0,639 0,035 Psychosexual dysfunction treatment
0,645 0,072 CC chemokine 2 receptor antagonist
0,598 0,033 Acetylcholine release stimulant
0,572 0,014 Hypertensive
0,623 0,067 CYP2D16 substrate
0,553 0,024 Cardiotonic
0,565 0,057 QT interval prolongation
0,549 0,058 Antiviral (Picornavirus)
0,512 0,028 Nephrotoxic
0,564 0,090 Cardiovascular analeptic
0,518 0,056 Adenylate cyclase stimulant
0,540 0,094 Antineurotoxic
0,504 0,060 Antiepileptic
0,507 0,082 Tocolytic
0,571 0,197 Cardioprotectant
0,515 0,200 Nerve growth factor agonist
EFFECTS
0,712 0,012 Antitoxic
0,540 0,094 Antineurotoxic
0,712 0,012 Hepatoprotectant
0,712 0,012 Membrane permeability inhibitor
0,553 0,024 Cardiotonic
0,553 0,024 Antiarrhythmic
0,553 0,024 Cardiotonic
0,553 0,024 Heart failure treatment
0,553 0,024 Cardiotonic
0,518 0,056 Adenylate cyclase stimulant
0,518 0,056 Adenylate cyclase stimulant
0,712 0,012 Antiinflammatory
0,712 0,012 Membrane permeability inhibitor
0,739 0,019 Arrhythmogenic
0,720 0,019 Torsades de pointes
0,712 0,012 Neuroprotector
0,712 0,012 Membrane permeability inhibitor
0,515 0,200 Nerve growth factor agonist
0,518 0,056 Ophthalmic drug
0,518 0,056 Antiglaucomic
0,518 0,056 Adenylate cyclase stimulant
0,660 0,025 Antiparkinsonian
0,660 0,025 Neurotransmitter uptake inhibitor
0,515 0,200 Nerve growth factor agonist
0,512 0,028 Toxic
0,512 0,028 Nephrotoxic
0,564 0,090 Analeptic
0,564 0,090 Cardiovascular analeptic
0,645 0,072 Antineurogenic pain
0,645 0,072 CC chemokine 2 receptor antagonist
0,598 0,033 Cognition disorders treatment

 

[shibireru]

That's cool. It's be even cooler if the reverse process were possible (i.e. listing the effects you desire and then getting a list of substances that might be able to achieve those effects).

Erythropoietin secretagogue
Adrenocorticotropic hormone receptor partial antagonist
Melanocortin 1, 3, and 4 receptor agonist
D2 agonist
Agonist of Tyrosine kinase B and C receptors
Upregulator of superoxide dismutase expression
Glial cell line-derived neurotrophic factor secretagogue
AMPA receptor partial agonist
Nicotinic acetylcholine alpha 7 agonist
Enkephalinase inhibitor
Mu-opioid receptor agonist (I know that this effect and that last would probably conflict with its AMPA and cholinergic activity)
5-HT2A & C antagonist
5-HT4 agonist
5-HT6 antagonist
(Still not sure which 5-HT1 receptors should be agonized and which antagonized - especially as regards post-synaptic and pre-synaptic forms.)
etc...

Such a substance will forever exist only within my dreams...

 

[Hammilton]

No, you're never going to find a drug that does all of that. You'll never find a drug that does all of what's predicted by PASS, either. Those are just probabilities based upon similarities to known substances.

And why do you want a D2 agonist? Do you fancy vomiting heavily?


Anyway, I've still not gotten any answer: Is anyone familiar with how it makes predictions of activity for things that may not match any 2D pharmacophore (as in the way the various PEAs do) but would when compared energy minimized in 3D?

 

[shibireru]

No, you're never going to find a drug that does all of that. You'll never find a drug that does all of what's predicted by PASS, either. Those are just probabilities based upon similarities to known substances.

I know that. That's why I wrote "Such a substance will forever exist only within my dreams... "

And why do you want a D2 agonist? Do you fancy vomiting heavily?

Hyperprolactinaemia. Could always throw in some domperidone?

 

[Hammilton]

I don't think using a D2 antagonist to block D2 agonism's emetic effects will result in any gain.

 

[shibireru]

Domperidone is a peripheral D2 antagonist.

 

[shibireru]

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1463696

To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre-treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti-parkinsonian response to a given dose of levodopa.

This is why I want to find a mu-opioid receptor antagonist impermeable to the blood-brain barrier. You'd probably get intensification of the euphoria and a vast attenuation of nausea and respiratory depression along with increased, rather than decreased gastrointestinal mobility, preventing the "shitting bricks" effect so often induced by opioids. In short, it would allow you to get so much more out of your scarce supplies.

 

[Hammilton]

Domperidone is a peripheral D2 antagonist.

And? It still causes hyperprolactinaemia. I can only assume that you weren't using the agonist to cause hyperprolactinaemia, which it wouldn't. If it's cause by peripheral antagonism, nonselective agonism won't do any good. Even peripherally selective agonism won't. I mean, this isn't something I know or care much about, but I don't understand the logic.

Braz J Med Biol Res. 1991;24(6):591-4.Links
Hyperprolactinemia induced by long-term domperidone treatment does not alter the sensitivity of striatal dopamine receptors.
Scavone C, DeLucia R, Dos-Santos LF.

Departamento de Farmacologia, Universidade de São Paulo, Brasil.

We investigated the effect of hyperprolactinemia induced by long-term domperidone treatment (10.0 mg/kg, single daily dose, ip) on striatal dopamine (DA) receptor sensitivity in male Wistar rats weighing 250-300 g (N = 8). Domperidone treatment for 7 days continued to produce an increase in serum concentration of prolactin (PRL) from 17.3 +/- 2.2 to 33.1 +/- 7.3 and from 16.8 +/- 2.3 to 21.9 +/- 2.1, 2 and 72 h after domperidone withdrawal, respectively. Hyperprolactinemia induced by long-term domperidone treatment did not change binding sites (Bmax) and dissociation constant (Kd) of [3H]-spiroperidol binding when compared to controls. These results show that hyperprolactinemia induced by long-term domperidone treatment does not effect the sensitivity of striatal DA receptors presumably because the effect of neuroleptic drugs is due to their interaction with the receptors and not to the concomitant hyperprolactinemia.

 

[The Monkey Mantra]

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1463696




This is why I want to find a mu-opioid receptor antagonist impermeable to the blood-brain barrier. You'd probably get intensification of the euphoria and a vast attenuation of nausea and respiratory depression along with increased, rather than decreased gastrointestinal mobility, preventing the "shitting bricks" effect so often induced by opioids. In short, it would allow you to get so much more out of your scarce supplies.

You'd still get the respiratory depression. That's a central effect, though someone correct me if there's not much barrier there. It'd help the nausea, maybe, just 'cause there's DEFINITELY not much of a barrier at the CTZ.

 

[Hammilton]

Yes, and the nausea as well.

 

[shibireru]

And? It still causes hyperprolactinaemia. I can only assume that you weren't using the agonist to cause hyperprolactinaemia, which it wouldn't. If it's cause by peripheral antagonism, nonselective agonism won't do any good. Even peripherally selective agonism won't. I mean, this isn't something I know or care much about, but I don't understand the logic.

I have the condition of mild hyperprolactinaemia which has diminished my libido. I would like to treat that. That means D2 agonists, such as cabergoline, bromocriptine, pramipexole, ropinirole, etc... Unfortunately, they can cause emesis and nausea, as you noted. My assumption was that it was their action on D2 receptors within the brain that produced a reduction of prolactin levels and their extracerebral action (i.e. their activity at the chemoreceptor trigger zone at the base of the brain) that produced nausea and so forth. Since Domperidone does not cross the blood-brain barrier, I also assumed that it could prevent or provide diminution of the side-effects of something like cabergoline, without reducing its therapeutic effects mediated by intracerebral D2 receptors.

My problem is that I was under the impression that the pituitary lay within the brain and not on its periphery unprotected by the blood-brain barrier. I see now that I was mistaken. Thank you for bursting yet another bubble.

 

[nuke]

What does it say about (2)-3-amino-3-(benzylamino)-1-(5-bromo-6-hydroxymorpholin-3-yl)prop-2-en-1-one?