Indian J Pharmacol. 2011 Sep;43(5):492-501. doi: 10.4103/0253-7613.84947.
Inverse agonism and its therapeutic significance.
Indian journal of pharmacology
Gurudas Khilnani, Ajeet Kumar Khilnani
Affiliations
Affiliations
- Department of Pharmacology, RNT Medical College, Udaipur, India.
PMID: 22021988
PMCID: PMC3195115 DOI: 10.4103/0253-7613.84947
Abstract
A large number of G-protein-coupled receptors (GPCRs) show varying degrees of basal or constitutive activity. This constitutive activity is usually minimal in natural receptors but is markedly observed in wild type and mutated (naturally or induced) receptors. According to conventional two-state drug receptor interaction model, binding of a ligand may initiate activity (agonist with varying degrees of positive intrinsic activity) or prevent the effect of an agonist (antagonist with zero intrinsic activity). Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity). Receptors of many classes (α-and β-adrenergic, histaminergic, GABAergic, serotoninergic, opiate, and angiotensin receptors) have shown basal activity in suitable in vitro models. Several drugs that have been conventionally classified as antagonists (β-blockers, antihistaminics) have shown inverse agonist effects on corresponding constitutively active receptors. Nearly all H(1) and H(2) antihistaminics (antagonists) have been shown to be inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level of inverse agonism as compared to propranolol and nadolol. Several antipsychotic drugs (D(2) receptors antagonist), antihypertensive (AT(1) receptor antagonists), antiserotoninergic drugs and opioid antagonists have significant inverse agonistic activity that contributes partly or wholly to their therapeutic value. Inverse agonism may also help explain the underlying mechanism of beneficial effects of carvedilol in congestive failure, naloxone-induced withdrawal syndrome in opioid dependence, clozapine in psychosis, and candesartan in cardiac hypertrophy. Understanding inverse agonisms has paved a way for newer drug development. It is now possible to develop agents, which have only desired therapeutic value and are devoid of unwanted adverse effect. Pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, attenuates psychosis in patients with Parkinson's disease with psychosis and is devoid of extrapyramidal side effects. This dissociation is also evident from the development of anxioselective benzodiazepines devoid of habit-forming potential. Hemopressin is a peptide ligand that acts as an antagonist as well as inverse agonist. This agent acts as an antinociceptive agent in different in vivo models of pain. Treatment of obesity by drugs having inverse agonist activity at CB(1/2) receptors is also underway. An exciting development is evaluation of β-blockers in chronic bronchial asthma-a condition akin to congestive heart failure where β-blockade has become the standard mode of therapy. Synthesis and evaluation of selective agents is underway. Therefore, inverse agonism is an important aspect of drug-receptor interaction and has immense untapped therapeutic potential.
Keywords: Constitutive activity; G-protein-coupled receptors; inverse agonism; inverse agonists
References
- Expert Rev Neurother. 2002 Mar;2(2):261-9 - PubMed
- Science. 1982 Jun 11;216(4551):1241-3 - PubMed
- Br J Pharmacol. 2008 Oct;155(4):494-504 - PubMed
- Br J Pharmacol. 1999 Jul;127(5):1099-104 - PubMed
- Mol Pharmacol. 2003 Aug;64(2):512-20 - PubMed
- Trends Pharmacol Sci. 2006 Feb;27(2):92-6 - PubMed
- J Pharmacol Exp Ther. 2000 Oct;295(1):226-32 - PubMed
- J Clin Invest. 2001 Apr;107(8):947-8 - PubMed
- Life Sci. 1994;54(20):PL339-50 - PubMed
- N Engl J Med. 2010 Apr 1;362(13):1169-71 - PubMed
- Mol Pharmacol. 2001 Mar;59(3):532-42 - PubMed
- Sleep. 2008 Dec;31(12):1663-71 - PubMed
- Eur J Pharmacol. 2000 Oct 6;406(1):R1-3 - PubMed
- Circulation. 2000 Apr 11;101(14):1634-7 - PubMed
- Endocrinology. 2004 Nov;145(11):5157-67 - PubMed
- Am J Respir Cell Mol Biol. 2008 Mar;38(3):256-62 - PubMed
- Proc Natl Acad Sci U S A. 1989 Oct;86(19):7321-5 - PubMed
- Annu Rev Pharmacol Toxicol. 2002;42:349-79 - PubMed
- Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4948-53 - PubMed
- Neuropsychopharmacology. 2010 Mar;35(4):881-92 - PubMed
- Annu Rev Med. 2004;55:27-39 - PubMed
- Circulation. 2000 Apr 11;101(14):1707-14 - PubMed
- Eur J Neurosci. 2003 Jan;17(2):307-14 - PubMed
- Psychopharmacology (Berl). 2005 May;179(2):461-9 - PubMed
- Mol Pharmacol. 1994 Mar;45(3):490-9 - PubMed
- Psychopharmacology (Berl). 1994 Jul;115(3):325-31 - PubMed
- Psychopharmacology (Berl). 2009 Mar;202(4):673-87 - PubMed
- Neuropharmacology. 2007 Sep;53(4):574-82 - PubMed
- J Pharmacol Exp Ther. 2004 Apr;309(1):102-8 - PubMed
- Clin Exp Allergy. 2002 Apr;32(4):489-98 - PubMed
- Neurosci Biobehav Rev. 2001 Mar;25(2):193-201 - PubMed
- Cancer Chemother Pharmacol. 2006 Jul;58(1):50-61 - PubMed
- Drugs. 2003;63(16):1697-741 - PubMed
- Mol Pharmacol. 2003 Dec;64(6):1357-69 - PubMed
- Nature. 2000 Dec 14;408(6814):860-4 - PubMed
- Science. 1990 Aug 10;249(4969):655-9 - PubMed
- J Biol Chem. 2004 Aug 13;279(33):34431-9 - PubMed
- J Pharmacol Exp Ther. 1998 Apr;285(1):119-26 - PubMed
- N Engl J Med. 2004 Nov 18;351(21):2203-17 - PubMed
- Clin Pharmacol Ther. 1976 May;19(5 Pt 1):493-501 - PubMed
- J Psychiatry Neurosci. 1994 Jan;19(1):24-9 - PubMed
- Trends Pharmacol Sci. 2001 Jun;22(6):273-6 - PubMed
- Circulation. 1996 Dec 1;94(11):2817-25 - PubMed
- Hypertens Res. 2009 Oct;32(10):875-83 - PubMed
- Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2719-23 - PubMed
- Naunyn Schmiedebergs Arch Pharmacol. 2008 Aug;378(2):149-69 - PubMed
- Br J Pharmacol. 2000 Jul;130(5):1131-9 - PubMed
- J Neural Transm (Vienna). 1996;103(10):1163-75 - PubMed
- Am J Gastroenterol. 1999 Feb;94(2):351-7 - PubMed
- Mol Pharmacol. 2000 Nov;58(5):887-94 - PubMed
- Br J Pharmacol. 2005 May;145(1):34-42 - PubMed
- Mol Pharmacol. 2001 Jul;60(1):53-62 - PubMed
- Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):393-9 - PubMed
- Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20588-93 - PubMed
- Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11354-8 - PubMed
- Cochrane Database Syst Rev. 2002;(1):CD002992 - PubMed
- Clin Exp Pharmacol Physiol. 2007 Mar;34(3):161-5 - PubMed
- N Engl J Med. 2001 May 31;344(22):1659-67 - PubMed
- Life Sci. 1996 May 24;58(26):PL381-9 - PubMed
- FASEB J. 2001 Mar;15(3):598-611 - PubMed
- Behav Pharmacol. 2003 Dec;14(8):573-82 - PubMed
- Br J Pharmacol. 1999 Feb;126(3):665-72 - PubMed
- Br J Pharmacol. 2008 Jan;153(2):226-39 - PubMed
- Eur Heart J. 1996 Apr;17 Suppl B:8-16 - PubMed
- Mol Pharmacol. 2001 Oct;60(4):712-7 - PubMed
- Circulation. 2000 Aug 1;102(5):484-6 - PubMed
Publication Types