Phil Skolnick

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Phil Skolnick (born 26 February 1947) is an American neuroscientist and pharmacologist most widely known for his work on the psychopharmacology of depression and anxiety, [1] as well as on addiction medicine. [2] Author of more than 500 published papers, Skolnick's most notable accomplishments include elucidating the role of the NMDA system in depression therapeutics, [3] demonstrating the existence of endogenous benzodiazepine receptor ligands, [4] and spearheading the National Institute on Drug Abuse's partnership to develop a naloxone atomizer for reversal of acute opioid overdose. [2] Skolnick's work also laid the foundation for the development of ketamine as a rapid-acting antidepressant. [5]

Contents

Early life and education

Raised in a Manhattan tenement, Skolnick attended Stuyvesant High School, one of New York City's most selective specialized high schools. Graduating at the age of 16, he began attending Long Island University in 1964. After graduating summa cum laude in 1968, [1] he attended George Washington University's school of medicine in Washington, D.C. receiving a PhD in pharmacology. [6]

Career

National Institutes of Health

Shortly after graduating from GWU in 1972, Skolnick was brought on as a staff fellow at what is now the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK), a subdivision of the National Institutes of Health (NIH), where he was mentored by John Daly. [1] In 1983, Skolnick became section chief of NIDDK's neurobiology laboratory, rising to the role of Chief of the NIDDK Laboratory of Neuroscience in 1986. During his time at NIH, Skolnick trained more than 75 postdocs. [1]

Anxiety: barbiturate and benzodiazepine systems

In 1981, Skolnick and colleague Steven M. Paul characterized the mechanism of action of benzodiazepines, showing that they act by modifying the efficacy of the brain's primary inhibitory neurotransmitter, GABA. [7] The following year, Skolnick and Paul, among other collaborators, showed that mammalian brain tissue contains endogenous ligands of the benzodiazepine receptor, some of the first evidence of so-called endozepines. [4] [8]

In 1985, not long after becoming section chief of NIDDK's neurobiology lab, [1] Skolnick and colleagues published work helping to characterize the mechanism of action of barbiturates, [9] which function as positive allosteric modulators at the GABAA receptor—a mechanism of action they share with benzodiazepines. Later, inspired by similarities between the electroencephalographic signatures associated with hepatic coma and benzodiazepine-induced coma, Skolnick hypothesized that impaired metabolism of endogenous benzodiazepine receptor ligands may play a role in producing the symptoms of hepatic encephalopathy. This hypothesis was borne out by experimental research, where it was shown that benzodiazepine receptor antagonists can temporarily alleviate some of the cognitive symptoms of fulminant hepatic failure. [10] [11]

NMDA systems, depression, aminoglycosides

By the late 1980s, it was known that certain types of stress induce a behavioral profile in animals that bears a strong resemblance to the symptoms of clinical depression, and that symptoms in this experimental model respond to antidepressants such as SSRIs. This depression-like effect arises, in part, through prolonged stimulation of the NMDA subtype of the glutamate receptor. [3] This led Skolnick and colleagues to discover in 1990 that inhibition of activity at the NMDA receptor (NMDAr) can prevent the development of this depression-like behavior, suggesting NMDA receptor antagonists—such as ketamine—as novel antidepressant therapies. [3]

In 1996, Skolnick and one of his postdoctoral students, Anthony Basile, developed the hypothesis that off-site activity of aminoglycoside antibiotics, which also have the potential to land on the NMDA receptor, might be responsible for the drugs' undesirable ototoxic side-effects. Skolnick and Basile proved this hypothesis by counteracting the ototoxic effects of aminoglycosides using an NMDAr antagonist. [1]

Eli Lilly & Company

In 1997, 25 years after joining the NIH, Skolnick was recruited by former collaborator Steven M. Paul to become a Lilly Fellow in Neuroscience at Eli Lilly & Company, where he worked toward the development of novel therapeutics for depression, applying the principles of rational drug design to synthesize and investigate new molecules. [12]

DOV Pharmaceuticals

In 2001, Skolnick left Lilly for the New Jersey-based DOV Pharmaceutical, where he acted as Chief Scientific Officer and Senior Vice President of Research. During his tenure at DOV, Skolnick oversaw development and testing of a variety of novel drugs, including the anti-anxiety candidate molecule DOV 51892—an "anxioselective" compound which is designed to produce the anxiety-alleviating effects of typical anxiolytics, but without the sedative side-effects usually characteristic of this class of drug. [13] In addition to his role as the CSO and Senior Vice President of Research, Skolnick became president of DOV Pharmaceutical in 2007 before departing in 2009. [14]

National Institute on Drug Abuse

After his tenure at DOV, Skolnick returned to the NIH in 2010, this time as the director of the National Institute on Drug Abuse's Division of Therapeutics and Medical Consequences (DTMC), which focuses largely on pharmacological therapies for addiction. Most notably, Skolnick's time at NIDA saw the FDA approval and deployment of the Narcan nasal spray tool, an easy-to-use opioid overdose reversal device developed in partnership with Lightlake Therapeutics. Narcan nasal spray is intended for distribution to the general public, [15] allowing the friends or family of an overdose victim to counteract the drug's effects almost immediately, without waiting for emergency response personnel to arrive. Many lives are lost due to drug users' hesitance to contact emergency services, a trend which Narcan nasal spray may help combat. [2]

Opiant Pharmaceuticals

In early 2017, Skolnick re-retired from NIH to serve as Chief Scientific Officer of Opiant Pharmaceuticals, Inc.—manufacturers of the Narcan nasal spray device. [16]

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

Colloquially known as "downers", depressants or central depressants are drugs that lower neurotransmission levels, or depress or reduce arousal or stimulation in various areas of the brain. Depressants do not change the mood or mental state of others. Stimulants, or "uppers", increase mental or physical function, hence the opposite drug class from depressants are stimulants, not antidepressants.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

<span class="mw-page-title-main">Neurosteroid</span> Compounds that affect neuronal excitability through modulation of specific ionotropic receptors

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP, SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

<span class="mw-page-title-main">Adinazolam</span> Triazolobenzodiazepine drug

Adinazolam is a tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never FDA approved and never made available to the public market; however, it has been sold as a designer drug.

An anxiogenic or panicogenic substance is one that causes anxiety. This effect is in contrast to anxiolytic agents, which inhibits anxiety. Together these categories of psychoactive compounds may be referred to as anxiotropic compounds.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Allopregnanolone</span> Endogenous inhibitory neurosteroid

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.

<span class="mw-page-title-main">Siramesine</span> Chemical compound

Siramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects. It was developed by the pharmaceutical company H Lundbeck for the treatment of anxiety, although development was discontinued after clinical trials showed a lack of efficacy in humans. Siramesine has been shown to produce an enhanced antidepressant effect when co-administered with NMDA antagonists. It has also been used to study the σ2 activity of cocaine, and has been shown to produce anticancer properties both in vitro and in vivo.

<span class="mw-page-title-main">Etifoxine</span> Anxiolytic medication

Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety. Administration is by mouth. Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions. In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods. Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination. Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins. Both mechanisms are conjectured to contribute to its anxiolytic properties.

In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.

<span class="mw-page-title-main">ZK-93423</span> Chemical compound

ZK-93423 is an anxiolytic drug from the β-Carboline family, closely related to abecarnil. It is a nonbenzodiazepine GABAA agonist which is not subtype selective and stimulates α1, α2, α3, and α5-subunit containing GABAA receptors equally. It has anticonvulsant, muscle relaxant and appetite stimulating properties comparable to benzodiazepine drugs. ZK-93423 has also been used as a base to develop new and improved beta-carboline derivatives and help map the binding site of the GABAA receptor.

<span class="mw-page-title-main">Ro5-4864</span> Chemical compound

Ro5-4864 (4'-chlorodiazepam) is a drug which is a benzodiazepine derivative of diazepam. However unlike most benzodiazepine derivatives, Ro5-4864 lacks affinity for GABAA receptors and lacks typical benzodiazepine effects, instead being sedative yet also convulsant and anxiogenic in effects. Ro5-4864 was found to be a potent ligand for the "peripheral benzodiazepine receptor", later renamed to mitochondrial translocator protein 18kDa (TSPO). Despite its convulsant effects, at lower doses Ro5-4864 has proved to be neuroprotective and has become widely used for research into the role of the TSPO protein in neurotoxicity. In vitro studies and rodent models also suggest the possibility of analgesic, antidepressant, cardioprotective, and anti-cancer effects.

<span class="mw-page-title-main">Pentylenetetrazol</span> Chemical compound

Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It has been used in convulsive therapy, and was found to be effective—primarily for depression—but side effects such as uncontrolled seizures were difficult to avoid. In 1939, pentylenetetrazol was replaced by electroconvulsive therapy, which is easier to administer, as the preferred method for inducing seizures in England's mental hospitals. In the US, its approval by the Food and Drug Administration was revoked in 1982. It is used in Italy as a cardio-respiratory stimulant in combination with codeine in a cough suppressant drug.

GABA<sub>A</sub> receptor positive allosteric modulator GABAA receptor positive modulators

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

<span class="mw-page-title-main">Fasedienol</span> Chemical compound

Fasedienol, also known as 4-androstadienol or as 4,16-androstadien-3β-ol, is a pherine which is under development by VistaGen Therapeutics in a nasal spray formulation (PRN) for the acute treatment of social anxiety disorder. It is also being investigated by VistaGen Therapeutics for the treatment of generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). The pherine is a positional isomer of the endogenous pheromone androstadienol. As of 2020, it is in phase III clinical trials for social anxiety disorder.

A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.

References

  1. 1 2 3 4 5 6 Ricks, Sharon (26 August 1997). "NIH Record". nihrecord.nih.gov. Archived from the original on 15 May 2015. Retrieved 25 February 2017.
  2. 1 2 3 Volkow, Nora (18 November 2015). "NARCAN Nasal Spray: Life-Saving Science at NIDA". About NIDA: Nora's Blog—drugabuse.gov. Retrieved 25 February 2017.
  3. 1 2 3 Trullas, R.; Skolnick, P. (1990-08-21). "Functional antagonists at the NMDA receptor complex exhibit antidepressant actions". European Journal of Pharmacology. 185 (1): 1–10. doi:10.1016/0014-2999(90)90204-j. ISSN   0014-2999. PMID   2171955.
  4. 1 2 Paul, S. M.; Marangos, P. J.; Skolnick, P.; Goodwin, F. K. (1982-01-01). "Biological substrates of anxiety: benzodiazepine receptors and endogenous ligands". L'Encéphale. 8 (2): 131–144. ISSN   0013-7006. PMID   6125374.
  5. ↑ Berman, R. M.; Cappiello, A.; Anand, A.; Oren, D. A.; Heninger, G. R.; Charney, D. S.; Krystal, J. H. (2000-02-15). "Antidepressant effects of ketamine in depressed patients". Biological Psychiatry. 47 (4): 351–354. doi:10.1016/s0006-3223(99)00230-9. ISSN   0006-3223. PMID   10686270. S2CID   43438286.
  6. ↑ "Opiant Pharmaceuticals, Inc. Announces the Appointment of Dr. Phil Skolnick as Chief Scientific Officer". NASDAQ GlobeNewswire (Press release). 6 February 2017. Retrieved 25 February 2017.
  7. ↑ Skolnick, P; Paul, SM (1981). "The mechanism(s) of action of the benzodiazepines". Medicinal Research Reviews. 1 (1): 3–22. doi:10.1002/med.2610010103. PMID   6125632. S2CID   41967995.
  8. ↑ Schmeck, Jr, Harold M. (7 September 1982). "The Biology of Fear and Anxiety: Evidence Points to Chemical Triggers". The New York Times.
  9. ↑ Schwartz, R. D.; Jackson, J. A.; Weigert, D.; Skolnick, P.; Paul, S. M. (1985-11-01). "Characterization of barbiturate-stimulated chloride efflux from rat brain synaptoneurosomes". The Journal of Neuroscience. 5 (11): 2963–2970. doi: 10.1523/jneurosci.05-11-02963.1985 . ISSN   0270-6474. PMC   6565157 . PMID   2997410.
  10. ↑ Bassett, M. L.; Mullen, K. D.; Skolnick, P.; Jones, E. A. (1987-11-01). "Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure". Gastroenterology. 93 (5): 1069–1077. doi: 10.1016/0016-5085(87)90571-3 . ISSN   0016-5085. PMID   2820828.
  11. ↑ Basile, A S; Pannell, L; Jaouni, T; Gammal, S H; Fales, H M; Jones, E A; Skolnick, P (1990-07-01). "Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy". Proceedings of the National Academy of Sciences of the United States of America. 87 (14): 5263–5267. Bibcode:1990PNAS...87.5263B. doi: 10.1073/pnas.87.14.5263 . ISSN   0027-8424. PMC   54303 . PMID   1973539.
  12. ↑ Skolnick, P. (1999-06-30). "Antidepressants for the new millennium". European Journal of Pharmacology. 375 (1–3): 31–40. doi:10.1016/s0014-2999(99)00330-1. ISSN   0014-2999. PMID   10443562.
  13. ↑ Popik, Piotr; Kostakis, Emmanuel; Krawczyk, Martyna; Nowak, Gabriel; Szewczyk, Bernadeta; Krieter, Philip; Chen, Zhengming; Russek, Shelley J.; Gibbs, Terrell T. (2006-12-01). "The anxioselective agent 7-(2-chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) is more efficacious than diazepam at enhancing GABA-gated currents at alpha1 subunit-containing GABAA receptors". The Journal of Pharmacology and Experimental Therapeutics. 319 (3): 1244–1252. doi:10.1124/jpet.106.107201. ISSN   0022-3565. PMID   16971504. S2CID   22057884.
  14. ↑ "Office of the DTMC Director". National Institutes on Drug Abuse. August 2016.
  15. ↑ "FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose". US Food & Drug Administration. 18 November 2015. Retrieved 25 February 2017.
  16. ↑ "Opiant Pharmaceuticals, Inc. Announces the Appointment of Dr. Phil Skolnick as Chief Scientific Officer". Opiant Pharmaceutical, Inc. 6 February 2017. Retrieved 25 February 2017.
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