By: Neal Shah

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There are two major classifications of drug-receptor activity: agonism and antagonism. Agonism occurs when a molecule binds to a receptor, causes an exertion of normal receptor operation, and eventually causes a response. Antagonism of a receptor occurs when a molecule binds to the receptor and does not allow activity to occur.1 Further divisions of these broad categories leads to a rich classification of molecular activity. Figure 1 (in PDF) provides a short, albeit incomplete, pharmacologically-relevant classification of agonism and antagonism relevant to this discussion, with drug examples.

Activation by benzodiazepines and barbiturates on GABAA receptors occur on sites where the natural ligand GABA does not bind. Since they do not share the same receptor site as the endogenous substance, this is defined as allosteric activation.1 Similarly, GABAA is allosterically inhibited by β-carboline, and subsequently causes seizures.2 Figure 2 (in PDF) shows the GABAA receptor binding pockets and drugs involved in activation.

Partial agonism by drugs like varenicline is helpful in overcoming addictive substances, such as nicotine (for smoking cessation). By providing a small release of dopamine in the mesolimbic region of the brain, nicotine withdrawal effects are diminished. An additive effect occurs when varenicline binds to the receptor, as it prevents nicotine from exerting its effect and makes smoking unnecessary.3 Similarly, buprenorphine partially activates the μ-opioid receptor, making opioid addiction treatment more tolerable and easier to overcome. Naloxone, a μ-opioid receptor antagonist, can be used to prevent abuse of buprenorphine.4 There are reports that naloxone may possess inverse agonist activity, as well.5

It should also be noted that antagonism is defined by some sources as “producing no effect when administered alone, but blocks the effects of agonists and inverse agonists.” This brings up a stimulating and difficult conceptual discussion as to how drugs are truly classified. For this definition to be true, it implies that some receptors are active at all times.6 If so, an antagonist would simply reduce receptor activity to a basal level. Figure 3 (in PDF) displays receptor activities after binding of an agonist, a partial agonist, an antagonist, or an inverse agonist.

For basal activity to occur, a small portion of receptors should be exhibiting some activity. There are receptors in the body that, in the absence of a ligand, exert an effect.7 These receptors respond to inverse agonists. When antagonists are administered, the receptors cannot exert any effect beyond its constitutive activity. Flexibility of receptor activity is preferred, rather than a traditional “on” or “off” receptor type that is commonly described. An analogy can also be drawn to a light switch and a dimmer switch. In this situation, the light switch is a receptor which can only exist in either an “on” or “off” state. When an agonist binds, an increase in the effect of the receptor is seen because it is in the “on” state, and when an antagonist is administered the receptor is in the “off” state so no effect is observed. An inverse agonist had no role in this situation.

On the other hand, constitutively-active receptors are more like dimmer switches: when an agonist is administered, the action a receptor exerts increases. When an inverse agonist is administered, effects seen would decrease from basal tones. Blood vessel activity is a physiological example of this analogy. Sympathetic innervations keep blood vessels partially constricted, representing basal or constitutive tone. Increases of sympathetic mediators act as full or partial agonists in Figure 3 (in PDF), constricting blood vessels further. Decreases in concentrations of the mediators would lead to vasodilation, represented by inverse agonists in Figure 3 (in PDF).8

Other pharmacologic examples are seen in the case of β1 receptors on cardiac tissues. β1 receptors have constitutive activity.9,10 Blocking β1 receptors with a competitive antagonist should not exert any effect, as per Figure 3. However, β1 blockers like nebivolol, carvedilol and bisoprolol—traditionally classified as competitive antagonists—cause bradycardia, thus exerting inverse agonist activity in human ventricular muscle.11-14 Upon discontinuation, exacerbation of β1 activity—termed as beta blocker withdrawal—is seen due to up-regulation of β1 receptors.

Another pharmacologic example of inverse agonists includes H1 antihistamines. Histamine is a crucial endogenous transmitter in the body, mediating wakefulness and cognitive ability, modulating appetite and maturation of immune cells, and participating in other physiologic processes.15 Histamine also mediates allergic responses to antigens, causing traditional urticaria, pruritis, and anaphylactic reactions (such as difficulty breathing and hypotension).16 Histamine can also increase secretions of gastric acid, leading to gastroesophageal reflux disease (GERD).17 Thus, histaminic receptors are constitutively active, and the H1 anti-histamine agents are rightfully termed “inverse agonists” instead of “competitive antagonists.”18

Diphenhydramine is a first-generation H1 antihistamine that acts as an inverse agonist at H1 receptors.19 It penetrates through the blood brain barrier, but it is not a substrate for the P-glycoprotein efflux pump. Inhibition of central histamine receptors causes the traditional sedative side effect, and it is for this reason that diphenhydramine is FDA approved for mild insomnia.20 It is also widely used to suppress allergic reactions. The desire to create an antihistamine agent that did not cause sedation lead to fexofenadine. Fexofenadine is a second generation H1 antihistamine that decreases allergic reactions mediated by histamine by acting as an inverse agonist to H1 receptors, similar to diphenhydramine. However, it is a P-glycoprotein substrate; so, if it does cross the blood brain barrier, it is pumped back out.21,22 This allows the same effects as diphenhydramine in terms of allergic reactions, but without sedative effects.

The H2 anti-histamine drug famotidine follows the same concept as its H1 antihistamine relatives. By decreasing basal/nocturnal secretions and large volumes of gastric acid, it can help with short term heartburn and gastroesophageal reflux disease treatments.23 Besides H1 and H2 inverse agonists, there is ongoing research on H3 and H4 receptors to treat neurological disorders. An H3 receptor inverse agonist known as pitolisant has been shown to increase alertness, and may prove beneficial for dementias, schizophrenia, or attention deficit hyperactivity disorder.24

Cannabinoid receptors, like histamine receptors, mediate appetite. Agonists, such as dronabinol, are used last-line in wasting diseases like cachexia.25 Cannabinoid agonists also have deleterious bone effects, and have been linked to impaired bone formation via the CB2 receptor.26 Inverse agonism of CB1 receptors in the central nervous system (CNS) and peripheral tissues suppresses food intake and promotes weight loss.27 A drug known as rimonabant has been developed as a CB1 inverse agonist; it is an anti-obesity agent for this reason.28 Cannabinoid receptors, again like histamine receptors, also modulate attentiveness. Rimonabant has been proven to increase cognitive ability, and may also be used for Parkinsonian disease states.29 CB2 inverse agonists are used to decrease bone loss by inhibition of osteoclastogenesis.30,31

The 5HT2A receptor has been implicated heavily in the psychosis model. Atypical antipsychotics act as inverse agonists of 5HT2A, and additionally act as inverse agonists at the 5HT2C receptor.32 A new 5HT2A inverse agonist, pimavanserin, acts to help with Parkinson’s disease psychosis where atypical antipsychotics may be contraindicated. It successfully reduced psychosis without causing significant decline in motor function in a small clinical trial conducted by Vanderbilt University.33 It is also being investigated for insomnia.35

In conclusion, inverse agonism is wholly different than antagonism. Whereas antagonism will return a receptor back to its basal activity, inverse agonism will depress receptor activity – thus providing advantages in pathological states of receptor hyperactivity. Currently, inverse agonists are commonly used for sedation and seizure control (with benzodiazepines) and allergic reactions (with anti-histamines). With further investigations, there will be increased utilization of inverse agonists.

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