resorcinol
02-16-2009, 04:10 PM
Receptor binding is a type of chemical reaction, an thus is subject to the same things that other chemical reactions are, such as kinetics, equilibrium, and bonding type.
The VAST majority of drugs that interact with integral neurotransmitter receptors (such as the mu opioid receptor or the CB1 receptor) form easily reversible bonds that are highly responsive to chemical equilibrium principles like Le Chatelier's Principle (in our case, with regard to that, we care mostly about how concentration of the reactants determines where the equilibrium will establish itself).
These easily reversible "bonds" aren't really chemical bonds at all in the traditional sense. They're not ionic, covalent, in between ionic and covalent, an certainly not metallic (metallic bonds are just a total delocalization of electrons in a mass of conductive metallic material caused by overlap of the conduction band with the valence band). These bonds are rather the result of intermolecular forces which are caused by the electromagnetic force (a subset of the electroweak interaction, which breaks into two [EM force an weak nuclear force] at low energies due to the fact that photons don't respond to higgs fields created by higgs bosons, and thus are massless, but W and Z bosons are strongly effected by higgs fields and thus have mass. If a force carrying boson has mass, the force it is responsible for will have a severely limited range. The EM force has infinite range in a inverse square fashion because the photon is massless). Some of the typical intermolecular forces that allow receptor "binding" are london dispersion forces (which cause periodic dipole moments), hydrophobic interactions (which causes hydrophobic portions of molecules to tend to clump together... this is important for receptors that have a hydrophobic pocket as those pockets will LOVE molecules with a hydrophobic region that fits nicely into the pocket), hydrogen "bonds" (not "bonds" at all really... just a very strong form of dipole-dipole interaction), plain old dipole-dipole interaction (between polar locations on molecules and receptors), and of course coordinate covalent bonding (a true bond, but easily reversible when plasma concentrations of the substance binding to the receptor fall).
There are a few (rare) cases where a receptor ligand forms a true covalent bond with a receptor. You would NOT want to take these drugs in the vast majority of cases. It's very uncertain what long term effects they could have on receptor expression. Examples for the mu opioid receptor are oxymorphazone (agonist) and naloxazone (antagonist). I seriously hope the gov't never catches wind of these covalent bond forming antagonists like naloxazone, because no doubt they'd have no problem subjecting opioid addicts to a drug with the potential to induce serious dysfunction of the endogenous opioid system in order to "MAKE SURE THEY STAY CLEAN!" -- since covalent bond forming mu antagonists CANNOT BE REVERSED or BROKEN THROUGH by ANY amount of AGONIST!!!!!! It's also strongly recommended that nobody take oxymorphazone. It will get you high for 48 hours or so the first time, but could have long term effects that would be very very unwanted, like extreme desensitization of mu receptors, decoupling of g-protein signaling molecules to a greater degree than even powerful agonists that are reversible like carfentanil can cause... etc. You wanna avoid these, period. The potent REVERSIBLE agonists are just fine an don't do possibly horrible things to the endogenous opioid system that irreversibles may.
The exception to this in with some enzyme inhibitors. In some cases, it's desirable to irreversibly bind, via covalent bond, to an enzyme's active site, for massively increased efficacy in enzyme inhibition and less reliance on half life to achieve steady pharmacodynamic effects. Irreversible covalent bond forming MAO inhibitors are a good example --- for the severest cases of depression and social phobia, they're absolutely unbeatable, especially for social phobia when combined with a benzodiazepine. Phenelzine (Nardil), and irreversible covalent bond forming MAOI, combined with clonazepam ---- is the BEST pharmacological treatment for social phobia if cognitive behavior therapy fails. There are downsides though .... the MAOI diet is a pain, and should it not work for somebody, 2 weeks must be given before another monoaminergic drug is given. MAOIs also make recreational drug use a huge no-no. Only weed and other synthetic CB1 agonists, SOME opioids (although respiratory depression is increased -- and pethidine (Demerol) is seriously contraindicated due to its secondary monoamine uptake inhibition and SS risk), ketamine, and ethanol are safe to use on MAOIs. Selegiline is irreversible too, but it's somewhat selective for MAO-B over MAO-A and when delivered transdermally (EMSAM), food issues are reduced (enough that, on the low dose, the MAOI diet is unnecessary... but it IS necessary on the higher doses). Some HIV protease an HIV integrase inhibitors are irreversible, which is extremely desirable and usually without increased side effects over the reversible inhibitors. These are enzymes however, and the body will make new ones once the irreversible inhibitor drug is stopped. Whether receptors are as robust and can be remade as easily isn't known with any kind of certainty... it's far too risky to take irreversible receptor binding drugs. MAO, for example, will reach normal levels 14 days or so after stopping an MAOI like selegiline or phenelzine.
So, receptor binding is mainly mediated by drug-receptor complex formation and un-formation by intermolecular force "bonding". Why is clonazepam FAR more potent than nitrazepam? That 2' Cl makes that region of the molecule much more electron dense and thus it has a much greater partial negative charge --- and the spot in the GABA(A)BZD receptor where benzos sit has a corresponding positive partial charge where 2' will approach... so having an electronegative atom there will increase potency.
The point basically is that drug-receptor binding is:
1) a chemical reaction
2) typically mediated by reversible intermolecular force "bonding" (not true chemical bonding), which is in turn mediated by the electromagnetic force (half of the electroweak interaction in the Standard Model of physics) due to molecules (drugs and the proteins that are receptors / enzymes) having an uneven distribution of charge. Even extremely NON polar molecules have occasional dipole moments; this is called london dispersion force. A certain CB1 agonist with NO heterocyclic substituants (it's just carbon an hydrogen atoms) demonstrates how london dispersion force and hydrophobic interactions can be enough to impart activity at a receptor. Heterocyclic atoms, strategically placed, however, no doubt can dramatically increase potency, selectivity, and even sometimes subjective feeling in the case of CNS drugs by adding areas of stronger partial negative charge to a molecule (and partial positive charge too... since that electronegative heterocyclic substituted atom is hogging electrons from somewhere else on the molecule).
3) That this binding is subject to chemical reaction fundamental properties: kinetics, equilibrium, etc.
The biggest thing I want to point out is that "binding" to a receptor is a convenient, but misleading, way to phrase this interaction. Binding implies a true chemical bond (ie covalent, ionic ... covalent in the case of biological chemistry for the most part), and the vast majority of the time no covalent bonding takes place; that is only desirable if one wants to completely disable an enzyme like described above. For example, nardil (phenelzine) has a short half life, like 2 hours, but its effects last 24/7/365... because the reaction to form the complex, which is a covalently bonded (irreversible) one, is so strongly favored that equilibrium drives the reaction to completion, so the enzyme is STILL disabled by covalently bonded phenelzine molecules to the active site of MAO long after phenelzine circulating in the plasma has been excreted.
That's all!
The VAST majority of drugs that interact with integral neurotransmitter receptors (such as the mu opioid receptor or the CB1 receptor) form easily reversible bonds that are highly responsive to chemical equilibrium principles like Le Chatelier's Principle (in our case, with regard to that, we care mostly about how concentration of the reactants determines where the equilibrium will establish itself).
These easily reversible "bonds" aren't really chemical bonds at all in the traditional sense. They're not ionic, covalent, in between ionic and covalent, an certainly not metallic (metallic bonds are just a total delocalization of electrons in a mass of conductive metallic material caused by overlap of the conduction band with the valence band). These bonds are rather the result of intermolecular forces which are caused by the electromagnetic force (a subset of the electroweak interaction, which breaks into two [EM force an weak nuclear force] at low energies due to the fact that photons don't respond to higgs fields created by higgs bosons, and thus are massless, but W and Z bosons are strongly effected by higgs fields and thus have mass. If a force carrying boson has mass, the force it is responsible for will have a severely limited range. The EM force has infinite range in a inverse square fashion because the photon is massless). Some of the typical intermolecular forces that allow receptor "binding" are london dispersion forces (which cause periodic dipole moments), hydrophobic interactions (which causes hydrophobic portions of molecules to tend to clump together... this is important for receptors that have a hydrophobic pocket as those pockets will LOVE molecules with a hydrophobic region that fits nicely into the pocket), hydrogen "bonds" (not "bonds" at all really... just a very strong form of dipole-dipole interaction), plain old dipole-dipole interaction (between polar locations on molecules and receptors), and of course coordinate covalent bonding (a true bond, but easily reversible when plasma concentrations of the substance binding to the receptor fall).
There are a few (rare) cases where a receptor ligand forms a true covalent bond with a receptor. You would NOT want to take these drugs in the vast majority of cases. It's very uncertain what long term effects they could have on receptor expression. Examples for the mu opioid receptor are oxymorphazone (agonist) and naloxazone (antagonist). I seriously hope the gov't never catches wind of these covalent bond forming antagonists like naloxazone, because no doubt they'd have no problem subjecting opioid addicts to a drug with the potential to induce serious dysfunction of the endogenous opioid system in order to "MAKE SURE THEY STAY CLEAN!" -- since covalent bond forming mu antagonists CANNOT BE REVERSED or BROKEN THROUGH by ANY amount of AGONIST!!!!!! It's also strongly recommended that nobody take oxymorphazone. It will get you high for 48 hours or so the first time, but could have long term effects that would be very very unwanted, like extreme desensitization of mu receptors, decoupling of g-protein signaling molecules to a greater degree than even powerful agonists that are reversible like carfentanil can cause... etc. You wanna avoid these, period. The potent REVERSIBLE agonists are just fine an don't do possibly horrible things to the endogenous opioid system that irreversibles may.
The exception to this in with some enzyme inhibitors. In some cases, it's desirable to irreversibly bind, via covalent bond, to an enzyme's active site, for massively increased efficacy in enzyme inhibition and less reliance on half life to achieve steady pharmacodynamic effects. Irreversible covalent bond forming MAO inhibitors are a good example --- for the severest cases of depression and social phobia, they're absolutely unbeatable, especially for social phobia when combined with a benzodiazepine. Phenelzine (Nardil), and irreversible covalent bond forming MAOI, combined with clonazepam ---- is the BEST pharmacological treatment for social phobia if cognitive behavior therapy fails. There are downsides though .... the MAOI diet is a pain, and should it not work for somebody, 2 weeks must be given before another monoaminergic drug is given. MAOIs also make recreational drug use a huge no-no. Only weed and other synthetic CB1 agonists, SOME opioids (although respiratory depression is increased -- and pethidine (Demerol) is seriously contraindicated due to its secondary monoamine uptake inhibition and SS risk), ketamine, and ethanol are safe to use on MAOIs. Selegiline is irreversible too, but it's somewhat selective for MAO-B over MAO-A and when delivered transdermally (EMSAM), food issues are reduced (enough that, on the low dose, the MAOI diet is unnecessary... but it IS necessary on the higher doses). Some HIV protease an HIV integrase inhibitors are irreversible, which is extremely desirable and usually without increased side effects over the reversible inhibitors. These are enzymes however, and the body will make new ones once the irreversible inhibitor drug is stopped. Whether receptors are as robust and can be remade as easily isn't known with any kind of certainty... it's far too risky to take irreversible receptor binding drugs. MAO, for example, will reach normal levels 14 days or so after stopping an MAOI like selegiline or phenelzine.
So, receptor binding is mainly mediated by drug-receptor complex formation and un-formation by intermolecular force "bonding". Why is clonazepam FAR more potent than nitrazepam? That 2' Cl makes that region of the molecule much more electron dense and thus it has a much greater partial negative charge --- and the spot in the GABA(A)BZD receptor where benzos sit has a corresponding positive partial charge where 2' will approach... so having an electronegative atom there will increase potency.
The point basically is that drug-receptor binding is:
1) a chemical reaction
2) typically mediated by reversible intermolecular force "bonding" (not true chemical bonding), which is in turn mediated by the electromagnetic force (half of the electroweak interaction in the Standard Model of physics) due to molecules (drugs and the proteins that are receptors / enzymes) having an uneven distribution of charge. Even extremely NON polar molecules have occasional dipole moments; this is called london dispersion force. A certain CB1 agonist with NO heterocyclic substituants (it's just carbon an hydrogen atoms) demonstrates how london dispersion force and hydrophobic interactions can be enough to impart activity at a receptor. Heterocyclic atoms, strategically placed, however, no doubt can dramatically increase potency, selectivity, and even sometimes subjective feeling in the case of CNS drugs by adding areas of stronger partial negative charge to a molecule (and partial positive charge too... since that electronegative heterocyclic substituted atom is hogging electrons from somewhere else on the molecule).
3) That this binding is subject to chemical reaction fundamental properties: kinetics, equilibrium, etc.
The biggest thing I want to point out is that "binding" to a receptor is a convenient, but misleading, way to phrase this interaction. Binding implies a true chemical bond (ie covalent, ionic ... covalent in the case of biological chemistry for the most part), and the vast majority of the time no covalent bonding takes place; that is only desirable if one wants to completely disable an enzyme like described above. For example, nardil (phenelzine) has a short half life, like 2 hours, but its effects last 24/7/365... because the reaction to form the complex, which is a covalently bonded (irreversible) one, is so strongly favored that equilibrium drives the reaction to completion, so the enzyme is STILL disabled by covalently bonded phenelzine molecules to the active site of MAO long after phenelzine circulating in the plasma has been excreted.
That's all!