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Inverse Agonists – what do they mean for psychiatry? David Nutt 1 – Stephen Stahl2 – Pierre Blier 3 – Filippo Drago 4 – Yossi Zohar 5 - Sue Wilson1. Centre for Psychiatry, Imperial College London Department ofPsychiatry,University of California San Diego, SanDiego, CA, USA3.Institute of Mental Health Research, The Royal Mental Health Care Centre, Ottawa, Canada4. Biometec, University of Catania School of Medicine, Catania, Italy5 Department of Psychiatry, ShebaMedicalCenter, andSacklerSchoolofMedicine, Tel Aviv University, TelHashomer, Israel Most psychiatrists who prescribe drugs are familiar with the basic concepts of receptor agonism and antagonism. The vast majority of drugs we use in our profession are antagonists i.e. they block something. Usually they block the effects of an endogenous neurotransmitter such dopamine in the treatment of schizophrenia or the serotonin transporter in the case of serotonin reuptake inhibitors for depression. Direct agonist drugs are less common because they are harder to use on account of tolerance development but include opioids for pain [mostly mu-opioid receptor agonists] and benzodiazepines for insomnia [that act as agonists or partial allosteric modulators at the benzodiazepine receptor].About 30 years researchers working in the benzodiazepine receptor field discovered drugs that had opposite actions to benzodiazepine agonists i.e. they caused rather than reduced anxiety and seizures in rodents [Nutt et al 1982; File et al 1982]. These were originally called contragonists but later the term inverse agonist gained acceptance [Nutt and Linnoila 1988]. The proof that the opposite actions of agonist and inverse agonist drugs were produced via the same receptor came with the discovery of flumazenil, a drug that blocked both sets of actions, and so was an antagonist at the benzodiazepine receptor [Nutt et al 1982]. Inverse agonism at the benzodiazepine receptor has since been demonstrated to reverse deficits in a human model of memory impairment [Nutt et al 2007], leading to one inverse agonist [basmisanil] being taken into clinical trials for cognitive impairments in Down’s syndrome.A prerequisite for a drug to be considered as an inverse agonist is that its receptor must have ongoing intrinsic level of activity in the absence of any ligand. For the benzodiazepine receptor, this is provided by the activity of the neurotransmitter GABA acting at the GABA-A receptor that is part of the larger macromolecular complex that also includes the benzodiazepine binding site. In the case of G-protein coupled receptors, this can be provided by constitutive activity of the receptor, i.e. activity in the absence of the transmitter ligand; an agonist then will increase activity of the receptor above its basal level, whereas an inverse agonist will decrease activity below its basal level (Kenakin, 2004).More recently inverse agonism has been reported in other biological systems, including calcium channels and G-protein linked receptors. One of the more interesting aspects of G-protein research has emerged with drugs acting on the serotonin (5-HT)2A receptor. Many drugs currently in use in psychiatry act as antagonists at the 5-HT2A receptor. The best example is risperidone that has ten-fold greater affinity at this receptor than at the dopamine D2 receptor [table 1], so that in clinical practice all 5-HT2A receptors are blocked by doses of 5 mg risperidone or above [PET ref]. Other drugs used in psychiatry with significant 5-HT2A blocking actions include amitriptyline, olanzapine, trazodone, mirtazapine and quetiapine – see table 1. However, this table also shows that many effective drugs for psychosis have such low affinity for the 5-HT2A receptor that in clinical practice this will not come into play.The fact that many drugs used for psychosis are 5-HT2A [as well as dopamine D2] receptor antagonists, coupled with the fact that agonists at the 5-HT2A receptor [e.g. LSD] are psychotomimetic has led many to wonder if antagonism of this receptor could in itself be therapeutic in psychosis. Trials with relatively pure 5-HT2A antagonists [e.g. volinanserin: MDL-100,907] showed insufficient efficacy across the wide population of patients with schizophrenia so these drugs were dropped from further development in this indication [Charney et al 2013]. Recently, however, the selective 5-HT2A antagonist pimavanserin [Nuplazid] has shown efficacy against the psychotic symptoms such as delusions and hallucinations in Parkinson's disease [Cummings et al 2014] and it recently gained FDA approval for this indication. Clearly there are great merits in having a drug that treats psychosis in Parkinson's disease without blocking the already impaired dopamine neurotransmission. The FDA data specification for pimavanserin, however, calls it an inverse agonist and this is what spurred us to write this editorial. The evidence that the inverse agonist claim for pimavanserin is built on comes from the test-tube where assays of 5-HT2A receptor function pimivanserin has the opposite action to those of a 5-HT2A agonist, i.e. it reduces as opposed to increases phospho-inositol production [Weiner et al 2001]. However in this paper, most other drugs already mentioned above as antagonists also had this action, suggesting they too should be called inverse agonists! So before the pharmacology of drugs used for psychosis and depression is completely re-written, these experimental measures should be re-examined in more detail.The bioassay used in these studies that have revealed inverse agonism uses a mutant human 5-HT2A receptor that exhibits constitutive activity, i.e. even at rest, it stimulates phospho-inositol production. This means that there is the option for both an increase and a decrease in production. However when non-mutant [wild-type] receptors are used, there is no constitutive activity and then these so-called inverse agonists behave as antagonists [Muntasir et al 2006]. They can block the effects of agonists such as LSD but have no activity of their own. The key question therefore is what happens in the human brain? Is there constitutive activity at human brain 5-HT2A receptors that would allow inverse agonists to have an effect? And if so, how could it be demonstrated?There are only a few ways to address this question. Serotonin2A antagonists have little impact on human brain functions other than increasing slow wave sleep [SWS] [Idzikowski et al 1987] and possibly enhancing 5-HT induced prolactin release [Charig et al 1986]. Neither of these, however, would be proof of inverse agonism as they could equally be explained by antagonism of endogenous 5-HT. One way to address this would be to demonstrate a significant difference between pimavanserin and other 5-HT2A antagonists on one of these variables. Even better would be to show, as was done in the case of the benzodiazepine inverse agonists, that the effects of the inverse agonist could be blocked by an antagonist [Nutt et al 1982]. The problem here is that there doesn’t appear to be any effect of pimavanserin, other than its anti-hallucination effect, that a pure antagonist could be tested against. Such a study would be practically as well as ethically challenging. Studies of the combination of pimavanserin and a low-dose of risperidone [which would predominantly act as a 5-HT2A antagonist] have if anything shown additive rather than competing actions [Meltzer et al 2012]. However this lack of blockade of pimavanserin could be explained by risperidone also being a 5-HT2A inverse agonist [so mimicking the actions of pimavanserin], rather than a 5-HT2A antagonist [which would be expected to block them]. Currently the best measure that might discriminate antagonist from inverse agonist properties would appear to be effects on sleep, especially SWS. Many drugs with 5-HT2A antagonist activity have had this sleep parameter measured and indeed some of these drugs, e.g. ritanserin and eplivanserin were tested in humans as sleep-promoting agents [Landolt and Wehrle 2009]. To properly address this question, one would require a comparison of a range of different antagonists on SWS at doses that give equivalent 5-HT2A brain receptor occupation. Sadly there are insufficient PET data to allow any reasonable attempt at this question as yet. However, there are SWS sleep data on a number of 5-HT2A antagonist drugs and these are presented in table 2. It can be seen that there is no clear relationship between the affinity of a drug for the 5-HT2A receptor and its effect on SWS. Moreover, there is no clear relationship between inverse agonism and SWS increase. Of particular interest is the comparison between pimavanserin and risperidone. Both have ultra high affinity at the 5-HT2A receptor and both are efficacious inverse agonists in cellular assays, yet pimavanserin enhances SWS whereas risperidone does not. Another challenge to the idea that 5-HT2A inverse agonism can be assessed by changes in SWS is trazodone which is a pure or neutral antagonist in-vitro but significantly enhances SWS. So where does this leave us with the concept of 5-HT2A receptor inverse agonists? As yet there are, to our knowledge, only in vitro assays for assaying inverse agonism. These are confounded – or rather based on – the existence of constitutive activity of the receptors in these cells lines. There is no evidence yet that such activity is seen in the human brain so even if drugs act as inverse agonists in cell systems they might simply be antagonists in humans. Moreover, the lack of a clear relationship between inverse agonist activity and increases in SWS [so far the only presumed effect of such inverse agonists measurable in humans] casts further doubt on the concept. Based on these facts, we feel it is premature to conclude that in humans pimavanserin or other 5-HT2A receptor blocking drugs are inverse agonists rather than antagonists. Refs Charig W, Anderson IM, Robinson JM, Nutt DJ, Cowen PJ (1986), L-typtophan and prolactin release: evidence for interaction between 5HT1 and 5HT2 receptors, Human Psychopharmacology 1: 93-97Charney DS, Nestler EJ, Sklar P, Buxbaum JD (2013). Neurobiology of Mental Illness. OUP USA. p.?767. ISBN?9780199934959.Cummings J, Isaacson S, Mills R, et al. Pimavanserin forpatients with Parkinson’s disease psychosis: a randomised,placebo-controlled phase 3 trial. Lancet. 2014; 383(9916): 533–540.File SE, Lister RG, Nutt DJ (1982), The anxiogenic action of benzodiazepine antagonists, Neuropharmacology 21: 1033-1037Idzikowski C, Cowen PJ, Nutt D, Mills FJ (1987), The effects of chronic ritanserin treatment on sleep and the neuroendocrine response to L-tryptophan, Psychopharmacology (Berl) 93: 416-420Kenakin T (April 2004). "Principles: receptor theory in pharmacology". Trends in Pharmacological Sciences 25 (4): 186–92.Landolt HP, Wehrle R (2009) Antagonism of serotonergic 5-HT2A?2C receptors: mutual improvement of sleep, cognition and mood? European Journal of Neuroscience, Vol. 29, pp. 1795–1809 Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day Schizophr Res. 2012 Nov;141(2-3):144-52. doi: 10.1016/j.schres.2012.07.029Muntasir HA, Bhuiyan MA, Ishiguro M, Ozaki M, Nagatomo T. (2006)Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor J Pharmacol Sci. 102:189-95. Nutt DJ, Cowen PJ, Little HJ (1982), Unusual interactions of benzodiazepine receptor antagonists, Nature 295: 436-438Nutt DJ, Linnoila M (1988) Neuroreceptor Science: A Clarification of Terms. Journal of Clinical Psychopharmacology 387-389Nutt DJ, Besson M, Wilson SJ, Dawson GR, Lingford-Hughes AR. (2007) Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist. Neuropharmacology 53(7):810-20. PMID: 17888460Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1- methylpiperidin-4-yl)-N′-(4 2ethylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006; 317(2): 910–918.Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR. (2001) 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther. 2001 299: 268-76.Table 1 Comparative affinity for 5-HT2A and dopamine D2 receptors for a range of drugs for psychosis and some selected antidepressants with high 5-HT2A affinity. All numbers nMolar. Drugs other than pimavanserin are ranked in order of 5-HT2A receptor affinity with those with highest at topDrugYellow hilite – inverse agonist 5-HT2A receptor affinity nM5-HT2A Inverse agonism status in-vitroDopamine D2 receptor affinity Relative affinity ratio 5-HT2A > D2Effects on SWS(less good data in brackets)Pimavanserin <1nM++++>1000nM>1000IncreaseDrugs for psychosis Asenapine<1N/A1.3 1.3N/ARisperidone <1++++3 3No changeZiprasidone <1N/A55IncreaseLurasidone2N/A21(No change)Olanzapine 2+++251/13IncreaseZotepine3N/A81/2N/AThioridazine 6+81(Increase)Clozapine 10++2001/20No changeAripiprazole 10N/A11/10N/AChlorpromazine 12++71.5N/APimozide14292N/AHaloperidol100+2 1/50No changeQuetiapine 120+6001/5No changeSulpiride10000101/100N/AAmisulpride2000011/1500N/ADrugs for depression Mirtazapine 20>1000>500No increaseAmitriptyline 180>1000>55No increaseTrazodone250>1000>40IncreaseOther DrugsRitanserin5++++IncreaseEplivanserin<1+++IncreaseVolinanserin(MDL100907<1++++Ketanserin8N/ANelotanserin<1IncreaseInverse agonist status from Weiner et al 2001 and Vanover et al 2006 ++++ IC50<1nM ++ +IC50 1-10nM ++ 10=100nM +> 100nM N/A = not available ................
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