Anxioselective Anxiolytics: on a Quest for the Holy Grail

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2012 Sep 18

PMID 22981367

Citations 45

Authors

Phil Skolnick

Affiliations

Soon will be listed here.

Abstract

The discovery of benzodiazepine receptors provided the impetus to discover and develop anxioselective anxiolytics ('Valium without the side effects'). The market potential for an anxioselective based on the γ-aminobutyric acid A (GABA(A)) receptor resulted in clinical trials of multiple compounds. In contrast to the anxioselective profile displayed in preclinical models, compounds such as bretazenil, TPA023, and MRK 409 produced benzodiazepine-like side effects (sedation, dizziness) in Phase I studies, whereas alpidem and ocinaplon exhibited many of the characteristics of an anxioselective in the clinic. Alpidem was briefly marketed for the treatment of anxiety, but was withdrawn because of liver toxicity. Reversible elevations in liver enzymes halted development of ocinaplon in Phase III. The clinical profiles of these two molecules demonstrate that it is possible to develop GABA(A) receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABA(A) receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning four decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines without the side effects that limit their usefulness.

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References

Barnard E, Skolnick P, Olsen R, Mohler H, Sieghart W, Biggio G . International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev. 1998; 50(2):291-313. View

Pribilla I, Neuhaus R, Huba R, Hillmann M, Turner J, Stephens D . Abecarnil is a full agonist at some, and a partial agonist at other recombinant GABAA receptor subtypes. Psychopharmacol Ser. 1993; 11:50-61. DOI: 10.1007/978-3-642-78451-4_5. View

McKernan R, Whiting P . Which GABAA-receptor subtypes really occur in the brain?. Trends Neurosci. 1996; 19(4):139-43. DOI: 10.1016/s0166-2236(96)80023-3. View

Low K, Crestani F, Keist R, Benke D, Brunig I, Benson J . Molecular and neuronal substrate for the selective attenuation of anxiety. Science. 2000; 290(5489):131-4. DOI: 10.1126/science.290.5489.131. View

Graham D, Arbilla S, Langer S . Expression and properties of recombinant alpha 1 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 forms of the rat GABAA receptor. Eur J Pharmacol. 1993; 246(3):283-7. DOI: 10.1016/0922-4106(93)90043-9. View

Kopp C, Rudolph U, Low K, Tobler I . Modulation of rhythmic brain activity by diazepam: GABA(A) receptor subtype and state specificity. Proc Natl Acad Sci U S A. 2004; 101(10):3674-9. PMC: 373521. DOI: 10.1073/pnas.0306975101. View

VOGEL J, Beer B, Clody D . A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia. 1971; 21(1):1-7. DOI: 10.1007/BF00403989. View

Atack J . Subtype-selective GABA(A) receptor modulation yields a novel pharmacological profile: the design and development of TPA023. Adv Pharmacol. 2010; 57:137-85. DOI: 10.1016/S1054-3589(08)57004-9. View

Atack J, Hallett D, Tye S, Wafford K, Ryan C, Sanabria-Bohorquez S . Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol. 2010; 25(3):329-44. DOI: 10.1177/0269881109354928. View

10.

Im H, Im W, Hamilton B, CARTER D, VonVoigtlander P . Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptors. Mol Pharmacol. 1993; 44(4):866-70. View

11.

Tobler I, Kopp C, Deboer T, Rudolph U . Diazepam-induced changes in sleep: role of the alpha 1 GABA(A) receptor subtype. Proc Natl Acad Sci U S A. 2001; 98(11):6464-9. PMC: 33491. DOI: 10.1073/pnas.111055398. View

12.

Patat A, Perault M, Vandel B, Danjou P, Brohier S, Zieleniuk I . Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers. J Psychopharmacol. 2012; 9(2):91-101. DOI: 10.1177/026988119500900203. View

13.

Smith A, Alder L, Silk J, Adkins C, Fletcher A, Scales T . Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux. Mol Pharmacol. 2001; 59(5):1108-18. DOI: 10.1124/mol.59.5.1108. View

14.

Pande A, Crockatt J, Feltner D, Janney C, Smith W, Weisler R . Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003; 160(3):533-40. DOI: 10.1176/appi.ajp.160.3.533. View

15.

Baty V, Denis B, Goudot C, Bas V, Renkes P, Bigard M . [Hepatitis induced by alpidem (Ananxyl). Four cases, one of them fatal]. Gastroenterol Clin Biol. 1994; 18(12):1129-31. View

16.

Lippa A, Coupet J, GREENBLATT E, Klepner C, Beer B . A synthetic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety. Pharmacol Biochem Behav. 1979; 11(1):99-106. DOI: 10.1016/0091-3057(79)90304-6. View

17.

Choi D, Farb D, Fischbach G . Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature. 1977; 269(5626):342-4. DOI: 10.1038/269342a0. View

18.

Lippa A, Klepner C, Yunger L, Sano M, Smith W, Beer B . Relationship between benzodiazepine receptors and experimental anxiety in rats. Pharmacol Biochem Behav. 1978; 9(6):853-6. DOI: 10.1016/0091-3057(78)90368-4. View

19.

Pollack M, Worthington J, Manfro G, Otto M, Zucker B . Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. J Clin Psychiatry. 1997; 58 Suppl 11:19-23. View

20.

Langer S, Arbilla S, Benavides J, Scatton B . Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes. Adv Biochem Psychopharmacol. 1990; 46:61-72. View