Basic Organic Chemistry and SAR MEGAthread

[Thetakishi]

Originally posted by our beloved Gun Lover on Zoklet.

Hello again, BLTC

As promised in my Pharmacological Jargon thread, I will now attempt to explain some basic organic chemistry and how it relates to pharmacology.

Keep in mind: the first portion of this thread is mostly for the uninitiated, or those who have a fledgling interest in psychopharmacology but are overwhelmed by some of the organic chemistry content.

Also, I am, by no means, the authority of organic chemistry on Zoklet: that title belongs to JoePedo, stateofhack, BungHole, beaker, King Owl, Hydroponichronic, or really any of the solid contributors to Flasks & Beakers. They just have better things to do than type out massive lectures on large doses of amphetamines.

Jargon Index:

Covalent Bond - A type of bond in which electrons are shared between a pair of atoms. Of the three types of chemical bonds possible (ionic, metallic, and covalent) most all the bonds encountered in organic molecules are covalent. All of the bonding I will be describing herein is of the covalent variety.

Hydrocarbon - any molecule that contains carbon and hydrogen only

Functional group - specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules (from wiki).

Valence Electron Shell - This the orbital(s) that the electrons occupy that are furthest away from an atom's nucleus.

Electronegativity - a measure of how greatly a given element attracts electrons toward itself.
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With that little portion out of the way, let's begin, shall we? Please note that if you've already learned organic chemistry, you should likely skip to part II. However, if you'd like to brush up on orbitals (or correct my ass), please give it a read.

Part I: Organic Chemistry

What is it and why should I care about it?
Organic chemistry is the science of carbon, hydrocarbons, and their derivatives.

Biological reactions involving staggering numbers of organic compounds are the reason you can even consciously comprehend this text. All life on earth can ultimately be traced back to the reactions of carbon-containing molecules coupled with other elements under the correct conditions.

Organic chemistry is awesome because it's a broad science deeply involved in the study of much of the cool shit in life: drugs, explosives, neurochemistry & consciousness, and plastics. Fuck yeah, what more could you ask for?

Why carbon?

Basically, carbon is special -- it has the ability to form an infinite number of quite stable covalent bonds with itself and other small elements, most commonly oxygen and nitrogen. This means carbon can form a staggering variety of compounds. For example, propane, a common gaseous fuel, consists of three carbons that are surrounded by hydrogen atoms (thus, a hydrocarbon), while the flexible plastic polypropylene is made up of a long string of repeating propane units.

Nomenclature

Organic nomenclature, or the systematic naming of organic molecules, is perhaps the most tedious facet of organic chemistry, as it is almost 100% memorization.

So what I'll do instead of devoting 10,000 written words to the subject, I'll direct you a series of videos that really helped me learn the basics:
http://www.youtube.com/watch?v=pMoA6...ayer_embedded#
Naming Simple Alkanes - YouTube
Video: click to display


If you want to delve deeper into nomenclature or organic chemistry as a whole, I encourage you to watch the entire series of videos for free at this URL:
http://www.khanacademy.org/#organic-chemistry


*****However, please note that if the above videos kill you with boredom, it will help your understanding of this thread greatly by at least referencing these simple charts after viewing the section on skeletal formulas later in this lesson:

Most important here, just grasp the correlation between number of carbons and the prefix that signifies this (e.g. meth = 1 carbon, eth = 2 carbon, but = 4 carbon, etc.)


Here is a list of various prefixes and suffixes that correspond to common organic functional groups. Combine the prefix, number of carbons, and suffix to describe most organic molecules. For instance, use the chart to name this molecule:

Spoiler: Click to toggle
Did you come up with ethoxybutanol? If not, I'll break it down:
Name the longest continuous carbon chain. I spot 4 carbons, so I know the parent chain will begin with but. Are the 4 carbons all singly bonded to each other? Yes, so we have an alkane. With this information, we can tell that the name of the longest continuous carbon chain is butane.

I also see an oxygen bonded to two different carbons, so we have an ether functional group. How many carbons are attached to that ether group? I see two carbons, so we have an ethoxy prefix on our molecule.

We have our prefix and number of carbons (ethoxybutane), but we're not done. There is also an -OH, or an alcohol functional group on the 4-carbon parent chain. Therefore we must drop the last letter, "e," from the name we have deciphered so far and replace it with the correct suffix denoting alcohols, -ol.

prefix (ethoxy) + longest carbon chain (butane) + suffix (ol) = ethoxybutanol


Valence Electrons and the Octet Rule

These are the electrons furthest away from an atom's nucleus. Because they are furthest away from the positively charged nucleus, the number of valence electrons an element has usually determines how many bonds it will form.

I'm going to attempt to explain molecular orbitals and chemical bonding as simply as possible, so keep in mind -- this particular subject gets very complex, but I will try to keep it to the essentials.

Look at this helpful picture:


In the top right section of the periodic table we have the major players in o chem: carbon, nitrogen, and oxygen. We also have fluorine, a notoriously toxic and reactive gas immediately following oxygen. 

Why is it that just after the most reactive element, fluorine, we see the most unreactive element, neon? The answer is fundamental to organic bonding. Notice that neon has the maximum of eight electrons in its outer shell. 

Known as the octet rule, it states that elements with a lower atomic number than element #20, calcium, tend to configure themselves in a way in which they will have eight electrons in their outermost valence shell, just like neon. They act in this manner due to thermodynamics: molecules naturally configure themselves into the lowest energy (i.e. most stable & unreactive) that the reaction conditions allow.

Glancing back at the picture above, we see that carbon needs four extra electrons to obey the octet rule and thus reach its desired stable configuration. Likewise, oxygen desires two extra electrons to fill its valence shell. This explains why together oxygen and hydrogen readily form H2O.

Keeping in mind the fact that carbon likes to form 4 bonds, let us continue on to how those electrons arrange themselves into various geometries.

Orbitals

Without getting too deep into this incredibly complex subject, orbitals are where the electrons of a given atom lie when in a molecule. One helpful thought to keep in mind is that like charges repel -- negatively charged electrons like to be as far away from each other as possible. 

*****We will be discussing both molecular geometry and electron geometry: Please note that electron geometry is dictated by the type of orbital, while molecular geometry depends on the presence or absence of lone electron pairs in a given orbital. Hopefully this will make sense after you read this section, but please keep in mind that the two concepts are not necessarily the same 

Skipping over the immense volume of theory, the most common orbitals encountered in organic chemistry are the following:

sp3 - carbon, in this hybridization, forms bonds to 4 different atoms giving a tetrahedral molecular geometry. 

Here's a picture of the simplest hydrocarbon, methane:


As you can see, the molecule takes on a tripod-esque tetrahedral geometry. It takes on this shape because the negative, electron-filled orbitals repel each other and are, in this tetrahedral configuration, furthest away from each other as possible.

A string of sp3 carbons coated in hydrogen is known as an alkane. It is also notable that the 4 bonds of sp3 carbons can rotate (this becomes important in the pharmacology portion).


sp2 - In the case of sp2 carbons, carbon bonds with three different atoms: two atoms are connected to carbon by a single bond while the third atom is connected by a double bond.

This orbital takes on the shape of a triangle, formally known as "trigonal planar." A carbon doubly bonded to another carbon is known as an alkene. For later on, it is also important to note that the double bond of a sp2 carbon can not rotate.

For example, the simplest alkene, ethene:


Here we see a flat (a.k.a. planar) molecule with a carbon-carbon double bond with hydrogens occupying the single bond positions. Though only bonding with three different atoms, each carbon donates two electrons to form the double bond, thus ethene obeys the octet rule. The green mass above the ethene molecule represents a part of the double bond. 

sp - Least common of the three major orbitals, sp carbon atoms contain a triple bond to another element: almost always carbon, nitrogen, or oxygen. 

Carbons that are triply bonded to another carbon are known as alkynes. We'll take a look at the simplest alkyne, ethyne:



As you can see, ethyne has a simple linear geometry. Because each alkyne carbon donates 3 of the 4 electrons needed to satisfy the octet rule, the single remaining orbital places itself as far away from those 6 electrons in that triple bond as possible, winding up 180 degrees opposite the triple bond.

Nitrogen and Oxygen:

So what about oxygen and nitrogen, didn't I say those were also really important? Both oxygen and nitrogen have more valence electrons than carbon, so how does this effect their shape? 

Having one more valence electron than carbon (5), nitrogen usually forms three bonds to gain a total of 8 to satisfy the octet rule. Although nitrogen with three single bonds possesses sp3 orbitals just like a carbon with four single bonds, unlike carbon it takes on what is called a trigonal pyramidal shape.


Shown above is NH3, better known as ammonia. It shows that while the electron geometry is characteristic of the sp3 tetrahedral geometry, the leftover pair of electrons slightly push the three bonds downward, leading to a triangular pyramid shape of the molecule. 

Oxygen, on the other hand, already has 6 of the 8 electrons it needs in order to satisfy the octet rule. Therefore oxygen almost always forms either two single bonds or one double bond with some other element. 

Like carbon and nitrogen, oxygens with only single bonds have sp3 orbitals. However, since it usually forms two single bonds as is the case for water or alcohols, the molecule takes on a "bent" configuration. 
A classic example of oxygen's bent geometry is water:


Akin to why the single lone pair of electrons on a sp3 nitrogen creates trigonal pyramidal molecular geometry, oxygen's two lone pairs force the electrons within the bonds downward into a bent molecular geometry.

Although oxygen only likes to form 2 bonds, it can form 3 and just like nitrogen, take on the the trigonal pyramidal molecular geometry.

When doubly bonded to another element, oxygen, like carbon, possesses the expected sp2 electron geometry of trigonal planar. However, since there are a lone pairs of electrons in each of the other sp2 orbitals that nothing bonds to, the molecular geometry appears linear.

What are those funny line drawings I've seen around here?

Now that I've hopefully explained the necessary prerequisites to understanding molecular geometry, we can get on to deciphering those dirty pictures us chemists fap to.

Drawings like these:


are a shorthand way of describing a compound's molecular structure. They are known as skeletal formulas. When organic molecules get large and complex, there really is no more convenient way to convey their structure than through this method.

In a skeletal formula, no carbon or hydrogen is explicitly shown (unless necessary -- see chirality in part II). That is, if you see a carbon (and only carbon) without 4 bonds shown, always assume hydrogen fills the void. Carbons are shown as the ends or vertices of single lines. 

I know it might sound a bit confusing at the moment, but let's practice just a little bit.

Now then, let's look at that glorious legal intoxicant, ethanol:
Shown below with all it's bonds we can plainly determine its molecular structure and orbital configuration:


See any carbons with any double or triple bonds? No, so we can definitively say the two carbons possess sp3 orbitals. However, does that picture show a real sp3 carbon with proper tetrahedral geometry? No it does not.

Now let's look at the skeletal formula:


Since we see only two carbons joined by a single bond, we should immediately think ethane. However, one of those carbons is also connected to an -OH alcohol group. Therefore we should drop the last letter of our ethane parent chain and replace it with -ol giving the proper name of the compound, ethanol.

Unlike the last depiction of ethanol, this one is not only quicker to draw, but also it shows the correct tetrahedral geometries of the carbon atoms.

So now that you have an idea why we use skeletal formulas, let's analyze that first sexy molecule in this section. We should now be able to predict the chemical formula, know the molecular geometries of each atom, and be able to name all the functional groups.



Go ahead and try it for fun. Once you're done, check the spoiler.
Spoiler: Click to toggle


Chemical formula: C20H25N3O




Common Functional Groups in Organic Chemistry:



Of those in the picture, the most commonly encountered in pharmacology are amines, amides, ketones, alcohols, esters, carboxylic acids, and alkenes. Alkanes are pervasive, but they're not much of a real functional group since they are very unreactive. However, it helps to be able to immediately recognize these groups when looking at an organic compound.

Common Organic Rings in Pharmacology

Benzene:

Also known as a phenyl ring when attached to another chain of carbons, this functional group is comprised of six carbon atoms each of which possess sp2 orbitals, giving the ring a flat, planar geometry. Because of its unique reactive properties and stability, phenyl groups are ubiquitous throughout the body.

Species of interest that feature a phenyl ring are the three neurotransmitters
dopamine, norepinephrine, and epinephrine.

Also included are the wide variety of Phenethylamine drugs like the 2C series of psychedelics.


Indole:


Indole is another common ring in drug science. It is the largest component of the neurotransmitter serotonin, as well as a principle component of the Tryptamine series of drugs.

Tryptamine:

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Thanks for reading. Hopefully I was able to help a few people better understand this stuff.

Part II on proteins/receptor stucture/SARs/Chirality soon to come. You're only allowed 20 images per post and I'm at the limit already. That and I'm coming down from that 4-FA I bombed 11 hours ago.

As always, feedback is appreciated and please point out my errors so I can fix them.

[Thetakishi]

Part II: Structure-Activity Relationships and Chirality 
Now that we know a sufficient amount of O Chem, it's time for the fun stuff. In this brief overview, I will attempt to describe how molecules interact with receptors at the molecular level. 

But first...
Hydrogen Bonding
In part 1, I forgot to talk about this important subject: hydrogen bonding.

Electronegativity was briefly discussed in part 1. As defined earlier, electronegativity is a measure of how greatly a given element attracts electrons toward itself. 

The three most electronegative elements are Nitrogen, Oxygen, and Fluorine. These three elements so greatly attract electrons that even if they already have a bond to hydrogen, their desire for electrons is not satiated. 
Quote:
Originally Posted by Wiki
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule
This type of bonding is the reason that your DNA base pairs stick together:


Three hydrogen bonds, denoted by the dotted line, keep the base pairs Guanine and Cytosine together.

Here's a chart showing examples of hydrogen bonding:


Any time you see an Oxygen---Hydrogen bond or a Nitrogen---Hydrogen bond, you have what is known as a Hydrogen-bond donor. However, since both nitrogen and oxygen contain lone pairs of electrons, they are Hydrogen-bond acceptors as well.

***From now on, any time you see an oxygen, nitrogen, or fluorine, look for potential hydrogen bonding!***

Now that that's done with...

Receptors: What Are They and How Do They Work? 

Almost all receptors are specialized proteins that cause some response when activated by a specific molecule or stimulus known as a ligand. 

What is a protein?

A protein is a special kind of molecule made up of amino acids. Amino acids are a set of small molecules that contain an amine and a carboxylic acidfunctional group, along with a side chain that corresponds to each respective amino acid.


In this picture we have a series of amino acids with different characteristics. For now, it's just important to spot the distinctive amine group and carboxylic acid.

So it turns out proteins are made up of thousands of these building blocks. Here's what a protein looks like unfolded and folded:


Because proteins are such massive molecules, scientists portray their shape in what is known as ribbon diagram. Here's an example to clarify this:



All three pictures represent the same protein; the first shows all amino acids drawn in skeletal form, the middle ribbon diagram shows its 3D shape, and the last one shows different chemical properties corresponding to each type of amino acid in the protein. Any given amino acid in a protein is called a residue.


So now that we have an idea of what proteins really are, we can look at special types of proteins known as receptors and see how molecules interact with them 

How do those tiny drug molecules interact with receptor proteins?

This is probably the question you've all been wanting answered. Provided you've been able to follow the other parts in this thread, this should click pretty easily.

Each G-protein coupled (GPCR) receptor we will discuss has what is known as an active site: this is where the endogenous neurotransmitters bind to activate or deactivate the receptor. The active site is comprised of a number of amino acid residues in a certain region among the receptor.

First we'll look at the Mu-opioid receptor:


On the right hand side, you'll see a mass of grey and yellow. The yellow portion is the active site and the grey part is the rest of the protein. The active site is color coded to match the specific properties of the active site's amino acid residues. 

Notice at the bottom that when an agonist binds to the active site, the whole receptor's shape is changed significantly. As a result, the receptor is activated and elicits a specific intracellular response, the mechanism of which is documented in the next section. 

Also note that when an antagonist binds, the receptor shape remains unchanged, but the active site is occupied and can't become activated by endogenous neurotransmitter ligands (like endorphins).

What happens when a receptor is activated?
When the residues of the active site are displaced by a molecule, they change the receptor's shape and cause changes to undergo on the inside of the cell.

For an in-depth analysis of what happens when receptors become active and change shape, please read this thread: GPCR signal transduction

In essence:
1. Ligand (drug or neurotransmitter) binds to G-protein coupled receptor
2. G-protein coupled receptor changes shape
3. G-protein dissociates from receptor
4. G-protein activates various kinase enzymes, causing chemical reactions inside the neuron.

Special cases: Allosteric Modulation

Not all drugs bind to the same active site as neurotransmitters. Some drugs bind to residues other than the official active site and still change the receptor's shape, if only just slightly. 

Let's take a look at the ionotropic GABAA receptor:


Refresher on ionotropic receptors:
Spoiler: Click to toggle
As a refresher, remember that ionotropic receptors greatly differ from G-protein coupled receptors. Their mechanism is much simpler than GPCRs.

Ionotropic receptor mechanism:
1. Ligand binds to active receptor site, opening a TINY pore.
2. Ions -- charged elements -- are allowed to flow in or out of the receptor.


Anyways, here we see a GABAA receptor. It is activated by the endogenous ligand GABA. However, when allosteric modulators like ethanol, barbituates, or benzodiazepines bind to residues other than the active site -- the one that GABA itself binds to -- the receptor's shape still changes. The site at which an allosteric modulator binds is known as a regulatory site.

For instance, when ethanol binds itself to the receptor, the receptor shape changes so that the endogenous ligand -- GABA -- binds more tightly, activating the receptor for longer and more often. Because drugs like ethanol, barbituates, and benzodiazepines effectively cause the endogenous ligand to have a greater effect, they are known as positive allosteric modulators.

It works both ways: allosteric modulators can either increase (positive) or decrease (negative) the affinity/efficacy of the natural ligand.

An example of a negative allosteric modulator would be strychnine, which prevents the neurotransmitter glycine from properly inhibiting your neurons, causing you to collapse in violent convulsions.

Putting It All Together: Pharmacophores

You've made it this far, so let's try to put all the pieces together!

Pharmacophore - "an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule" -- Wiki

In more understandable terms, a pharmacophore is a description of molecular features necessary for any given chemical compound to activate a receptor.

Let's start off simple and precise, here is a pharmacophore for the aforementioned GABAA receptor:


Overlayed onto one another are two molecules that bind to the benzodiazepine allosteric regulatory site on GABAA. In white, blue, and red is the prototypical benzodiazepine, diazepam (a.k.a. Valium). In green, blue, and red we have the experimental anxiolytic drug, CGS-9896.

White/Green = Carbon
Blue = Nitrogen
Red = Oxygen
Quote:
Originally Posted by Wiki
The red spheres labeled H1 and H2/A3 are, respectively, hydrogen bond donating and accepting sites in the receptor, while L1, L2, and L3 denote lipophilic binding sites
Remember that lipophilic = non-polar. Because both drugs have that oxygen that bonds to H1 spaced 3 atoms away from the nitrogen that bonds to H2/A3, the two molecules have a similar affinity for the receptor. Because they also both have nothing but lipophilic carbons in the L1 & L2 region, the drugs will elicit a very similar effect.

This basically means that even though the two drugs have an extremely different structure, they act upon the same receptor because they have key atoms or groups in the correct places. Cool, huh? This means that new drugs can be designed to have those key atoms or groups and bypass any structural laws.

If I've done a decent enough job explaining, you might be able to grasp this last bit:
Spoiler: Click to toggle

Getting more complex, here is a pharmacophore for an experimental anticoagulant (blood thinning) drug that binds to an enzyme (a special type of protein):




Notice all those colored circles around the molecule; those represent the 19 amino acids that make up the active site. While the three letter name denotes an abbreviation for the name of the amino acid, the color of the circles denotes the amino acid's chemical properties.

The dotted line shows everywhere the drug physically touches the receptor. Blue halos represent the degree of interaction with the receptor.

This in mind, let's take a look at the Glycine "Gly218" residue. 

Glycine itself:


That amine nitrogen forms a hydrogen bond with the doubly bonded oxygen of the drug right next to it. There are 18 other interactions, but they all rely on the same concept of polar and non-polar interactions.

For the sane: Please read this to verify that I'm not talking out of my ass.


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Alright, so that's it. I know I've gotten a bit unintelligable towards the end, so please ask me to clarify correct any mistakes.

Ask me anything at all, I obviously love discussing this topic.

Finally, props to anyone who reads the entire thing! I sure hoped you learned something new !

[Thetakishi]

Damn, the pictures didn't copy over. This one is going to be a pain in the ass to edit correctly. lol