Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor-agonist coupling.

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.^[1] In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally-defined binding sites on receptors.^[2] Because antagonists often disrupt the normal connectivity between neurons, their long-term, chronic use has been linked to neuronal death and very strong antagonists can be considered to be toxic.^[3]

Receptors[link]

Biochemical receptors are large protein molecules that can be activated by the binding of a ligand (such as a hormone or drug).^[4] Receptors can be membrane-bound, occurring on the cell membrane of cells, or intracellular, such as on the nucleus or mitochondrion. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly.^[4] The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites.^[5] Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site.^[6] In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects.^[6][7][8]

The term antagonist was originally coined to describe different profiles of drug effects.^[9] The biochemical definition of a receptor antagonist was introduced by Ariens^[10] and Stephenson^[11] in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by 'blocking' the receptor from the agonist. This definition also remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H₁ receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by β-adrenergic receptor activation.

Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states.^[12] The discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others.^[13] This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug.^[13]

Pharmacodynamics[link]

Efficacy and potency[link]

By definition, antagonists display no efficacy^[11] to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.^[4] The potency of an antagonist is usually defined by its IC₅₀ value. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC₅₀ value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar.^[14] The lower the IC₅₀ the greater the potency of the antagonist, and the lower the concentration of drug that is required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects.^[15]

Affinity[link]

The affinity of an antagonist for its binding site (K_i), i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and K_i determination is independent of the affinity, efficacy or concentration of the agonist used. However, it is important that equilibrium has been reached. The effects of receptor desensitization on reaching equilibrium must also be taken into account. The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression.^[16][17] Schild regression involves comparing the change in the dose ratio, the ratio of the EC₅₀ of an agonist alone compared to the EC₅₀ in the presence of a competitive antagonist as determined on a dose response curve. Altering the amount of antagonist used in the assay can alter the dose ratio. In Schild regression, a plot is made of the log(dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations.^[18] The affinity or K_i is where the line cuts the x-axis on the regression plot. Whereas, with Schild regression, antagonist concentration is varied in experiments used to derive K_i values from the Cheng-Prusoff equation, agonist concentrations are varied. Affinity for competitive agonists and antagonists is related by the Cheng-Prusoff factor used to calculate the K_i (affinity constant for an antagonist) from the shift in IC₅₀ that occurs during competitive inhibition.^[19] The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists.^[15]

Types[link]

Competitive[link]

Competitive antagonists (also known as surmountable antagonists) reversibly bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy.^[15] In functional assays using competitive antagonists, a parallel rightward shifts of agonist dose–response curves with no alteration of the maximal response is observed.^[20]

The interleukin-1 receptor antagonist, IL-1Ra is an example of a competitive antagonist.^[21] The effects of a competitive antagonist may be overcome by increasing the concentration of agonist. Often (though not always) these antagonists possess a very similar chemical structure to that of the agonist.

Non-competitive[link]

The term "non-competitive antagonism" (sometimes called non-surmountable antagonists)^{[citation needed]} can be used to describe two distinct phenomena: one in which the antagonist binds to the active site of the receptor, and one in which the antagonist binds to an allosteric site of the receptor.^[22] While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced.^[20] The rightward shift will occur as a result of a receptor reserve (also known as spare receptors).^[11] and inhibition of the agonist response will only occur when this reserve is depleted.

An antagonist that binds to the active site of a receptor is said to be "non-competitive" if the bond between the active site and the antagonist is irreversible or nearly so.^[22] This usage of the term "non-competitive" may not be ideal, however, since the term "irreversible competitive anatagonism" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of "non-competitive antagonism" discussed below.

The second form of "non-competitive antagonists" act at an allosteric site.^[22] These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds.^[23] Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor.^[24]

Uncompetitive[link]

Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which "the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist".^[25] Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor.^[26]

Silent antagonists[link]

Silent antagonists are competitive receptor antagonists that have zero intrinsic activity for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists or inverse agonists.

Partial agonists[link]

Partial agonists are defined as drugs that, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist in the presence of a full agonist, as it competes with the full agonist for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone.^[27][28] Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists.^[29][30] Buprenorphine, a partial agonist of the μ-opioid receptor, binds with weak morphine-like activity and is used clinically as an analgesic in pain management and as an alternative to methadone in the treatment of opioid dependence.^[31]

Inverse agonists[link]

An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors.^[32][33] Antihistamines, originally classified as antagonists of histamine H₁ receptors have been reclassified as inverse agonists.^[34]

Reversibility[link]

Many antagonists are reversible antagonists that, like most agonists, will bind and unbind a receptor at rates determined by receptor-ligand kinetics.

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors. Phenoxybenzamine is an example of an irreversible alpha blocker—it permanently binds to α adrenergic receptors, preventing adrenaline and noradrenaline from binding.^[35] Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs, as effects of non-competitive antagonists are reversible and activity of agonist will be restored.^[20]

Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist.^[14] For some antagonist, there may be a distinct period during which they behave competitively (regardless of basal efficiacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics. But, once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration–effect curve to the right, but, in general, both a decrease in slope and a reduced maximum are obtained.^[14]

See also[link]

Pharmacy and Pharmacology portal

• Affinity
• Agonist
• Efficacy
• Enzyme inhibitor
• Inverse agonist
• Mixed agonist/antagonist
• Receptor theory

References[link]

Sanjay Gupta
Sanjay Gupta
Born	(1969-10-23) October 23, 1969 (age 42) Novi, Michigan, United States[1]
Alma mater	University of Michigan Health System (Residency), University of Michigan Medical School (M.D.), University of Michigan (B.S.)
Occupation	Academic, journalist and neurosurgeon
Spouse	Rebecca Olson Gupta
Children	3

Sanjay Gupta ( /ˈsɑːndʒeɪ ˈɡuːptə/ SAHN-jay GOOP-tə; born October 23, 1969) is an American neurosurgeon and an assistant professor of neurosurgery at Emory University School of Medicine and associate chief of the neurosurgery service at Grady Memorial Hospital in Atlanta, Georgia.

Known as a media personality on health-related issues, he is best known as CNN's multiple Emmy award winning chief medical correspondent, hosting the network's weekend health program Sanjay Gupta, M.D., and making frequent appearances on their American Morning, Larry King Live and Anderson Cooper 360° programs. His reports from Charity Hospital, New Orleans, Louisiana, in the wake of Hurricane Katrina helped the hospital to win a 2006 Emmy Award for "Outstanding Feature Story in a Regularly Scheduled Newscast". Additionally, Gupta publishes a column in Time magazine and is a special correspondent for CBS News. His books Chasing Life and Cheating Death were New York Times and national bestsellers.^[2][3] His latest book, Monday Mornings, a novel, was released in March, 2012 and became an instant New York Times Bestseller. It is currently being adapted as a television show with David E. Kelley and Gupta serving as Executive Producers.

From 1997 to 1998, he served as one of fifteen White House Fellows, primarily as an advisor to Hillary Clinton. In January 2009, it was reported that Gupta was offered the position of Surgeon General of the United States in the Obama administration,^[1] but he withdrew his name from consideration.^[4] In January 2011, he was named "one of the 10 most influential celebrities" by Forbes magazine.^[5]

Life and career[link]

Youth[link]

Gupta was raised on 8 Mile Road in Novi, Michigan, in Oakland County in metro Detroit. His parents, Subhash and Damyanti Gupta, moved from India to Michigan, along with his older brother, Yogesh Gupta, to work as engineers for the Ford Motor Company in Dearborn, Michigan in the 1960s. His mother was the first female engineer to work in Ford Motor Company. He graduated from Novi High School in 1986. Gupta received his Bachelor of Science degree in biomedical sciences at the University of Michigan in Ann Arbor, and his Doctor of Medicine from the University of Michigan Medical School in 1993. As an undergraduate, he worked as an orientation leader for the freshman orientation program, and was a member of the Men's Glee Club. He also served as President of the Indian American Students Association (IASA), which is now the second largest student organization at U-M^[6]. He completed his residency in neurological surgery within the University of Michigan Health System in 2000.^[7] On April 28th, 2012, Gupta was awarded an honorary Doctor of Humane Letters degree for his accomplishments in the medical field. Gupta also gave the commencement address at the spring commencement ceremony held in the University of Michigan Stadium ^[8] to a crowd of about 45,000 people.

Broadcast journalism[link]

In 2003, Gupta traveled to Iraq to cover the medical aspects of 2003 invasion of Iraq. While in Iraq, Gupta performed emergency surgery on both U.S. soldiers and Iraqi civilians.^[9] Gupta was embedded with a Navy medical unit at the time, specifically a group of doctors called the “Devil Docs,” who supported the 1st Marine Expeditionary Force.^[10] A Marine named Jesus Vidana suffered a severe head injury, and the Marines asked for Gupta's assistance because of his background in neurosurgery. Vidana survived and was sent back to the United States for rehabilitation.^[9]

Gupta was named one of the Sexiest Men of 2003 by People magazine.^[2]

In December 2006, CBS News president Sean McManus negotiated a deal with CNN that would have Gupta file up to ten reports a year for the CBS Evening News with Katie Couric and 60 Minutes while remaining CNN's chief medical correspondent and associate chief of neurosurgery at Grady Memorial Hospital.

On October 14, 2007, Gupta guest-hosted a health episode of CBS News Sunday Morning as its regular host Charles Osgood was on vacation. In February 2009, Gupta hosted AC360 covering the White House Health Summit. He also guest hosted Larry King Live in October 2009. In January 2010, Gupta and Cooper led CNN's coverage of the earthquake in Haiti. Gupta has regularly appeared on the Late Show with David Letterman,^[11] The Late Late Show with Craig Ferguson,^[12] The Daily Show with Jon Stewart,^[13] Real Time with Bill Maher and The Oprah Winfrey Show.^[14] Winfrey referred to Gupta as CNN's hero in January 2010.^[15]

Surgeon General candidate[link]

On January 6, 2009, CNN announced that Gupta had been offered the position of Surgeon General by President Barack Obama.^[16]

Some doctors said that his communication skills and high profile would allow him to highlight medical issues and prioritize medical reform. However, others raised concerns about potential conflicts of interest with drug companies who have sponsored his broadcasts and his lack of skepticism in weighing the costs and benefits of medical treatments.^{[17][dead link]}

Representative John Conyers, Jr. (D-MI), wrote a letter opposing Gupta's nomination. Conyers supports a single-payer health care system, the sort that Conyers' filmmaker friend Michael Moore advocated in his documentary Sicko; Gupta has criticized Moore and the film.^[18]

Others, such as liberal commentator Jane Hamsher, defended the appointment, noting that Gupta's responsibilities as a surgeon general would be not that different from those of his CNN position, and that Gupta's media presence would make him ideal for the position.^[19] From the medical community, Donna Wright, of Creative Health Care Management, a regular commentator on medicine and politics, also defended the appointment on the grounds of his media presence, combined with his medical qualifications, which she viewed as an ideal combination for the post of surgeon general.^[20] Likewise, Fred Sanfilippo, executive vice president for health affairs at Emory University, supported Gupta's nomination by issuing a press release saying, "He has the character, training, intelligence and communications skills needed to help the United States improve its health and health care delivery systems in the next Administration."^[21] The American Council on Exercise, listed by PR Newswire as "America's leading authority on fitness and one of the largest fitness certification, education and training organizations in the world", endorsed the nomination of Gupta "because of his passion for inspiring Americans to lead healthier, more active lives." The ACE sent a letter of support to Senator Edward M. Kennedy.^[22] Former surgeon general Joycelyn Elders also supported Gupta's nomination, saying "He has enough well-trained, well-qualified public health people to teach him the things he needs to do the job."^[23] In March 2009 Gupta withdrew his name from consideration for the post, citing his family and his career.^[4]

Personal life[link]

Gupta is married to Rebecca Olson, a family law attorney. They were married in 2004 in a Hindu wedding ceremony. They live in Atlanta^[24] and have three daughters.^[25]

Medical practice[link]

Gupta is an Emory Healthcare general neurosurgeon at Grady Memorial Hospital and has worked on spine, trauma and 3-D-image-guided operations. He has published medical journal articles on percutaneous pedicle screw placement,^[26][27] brain tumors, and spinal cord abnormalities.^[28][29] He is licensed to practice medicine in New York, Michigan, Georgia and South Carolina.^[30]

Gupta (third from left) with Henri Ford (second from left) and two U.S. Navy doctors operating on a 12-year-old girl aboard the USS Carl Vinson.^[31]

During his reporting in Haiti following the January 2010 earthquake, Gupta received a call from the aircraft carrier USS Carl Vinson that an earthquake victim, a 12-year-old girl, was aboard and needed a neurosurgeon. Gupta, pediatric surgeon Henri Ford, and two U.S. Navy doctors removed a piece of concrete from the girl's skull in an operation performed aboard the Vinson.^[32][33] Ford later wrote that Gupta "proved to be a competent neurosurgeon."^[34]

Controversy[link]

Criticism of reporting[link]

Some journalists and journalism professors specializing in health care have criticized Gupta's coverage. Trudy Lieberman, a regular Nation contributor on healthcare and director of the health and medicine reporting program at the CUNY Graduate School of Journalism,^[35] reviewed Gupta's "ineptitude" in reporting on the McCain health plan. Lieberman criticized Gupta for relying on insurance industry statistics, and a health expert quoted by Lieberman said that Gupta's reporting “gives a gross oversimplification."^[36]

Peter Aldhous criticized Gupta's "enthusiasm for many forms of medical screening – even when the scientific evidence indicates that it may not benefit patients." He and other medical journalists accuse him of a "pro-screening bias" in promoting widespread electrocardiogram and prostate cancer screening, even though medical authorities like the US Preventive Services Task Force recommend against it.^[37]

Others have criticized Gupta's promotion of Merck's cervical cancer vaccine Gardasil, without disclosing the financial arrangements between CNN and Merck.^[38]

Gary Schwitzer, professor of health journalism at the University of Minnesota School of Journalism, has also criticized Gupta's reporting.^[39][40]

Michael Moore dispute[link]

A July 9, 2007, broadcast of CNN's The Situation Room aired a fact-check segment by Gupta on Michael Moore's 2007 film Sicko in which Gupta stated that Moore had "fudged facts".^[41]

Immediately following the segment, Moore was interviewed live on CNN by Wolf Blitzer. Moore said that Gupta's report was inaccurate and biased, and Moore later posted a detailed response on his website.^[42] Moore accused CNN of being biased in favor of the drug industry because most of the sponsors for their medical coverage were drug companies.

On July 10, 2007, Gupta debated Moore on Larry King Live; on July 15, CNN released a statement in response to Michael Moore's rebuttal.^[43] In it, they apologized for an error in their on-air report, having stated that in the film Moore reported Cuba spends $25 per person for health care when the film actually gave that number as $251. CNN attributed this to a transcription error. CNN defended the rest of Gupta's report and issued a point-by-point response to Moore's response in which CNN contended that Moore's comparison of data from different sources in different years was in effect "cherry picking" results, at the cost of statistical accuracy.

See also[link]

• List of American print journalists
• List of surgeons
• List of television reporters

References[link]

External links[link]

Wikimedia Commons has media related to: Sanjay Gupta

• Sanjay Gupta at the Internet Movie Database
• Sanjay Gupta CNN biography
• Sanjay Gupta on Twitter
• Interview with Dr. Sanjay Gupta
• Paging Dr. Gupta: – Blogs from CNN.com
• Web page at Emory Neurosurgery department
• Sanjay Gupta physician profile – Emory Neurosurgery