SB-221284

Last updated

SB-221284
SB 221284.svg
Clinical data
Other namesSB221284
Drug class Serotonin 5-HT2C receptor antagonist; Serotonin 5-HT2B receptor antagonist
Identifiers
  • 5-methylsulfanyl-N-pyridin-3-yl-6-(trifluoromethyl)-2,3-dihydroindole-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H14F3N3OS
Molar mass 353.36 g·mol−1
3D model (JSmol)
  • CSC1=C(C=C2C(=C1)CCN2C(=O)NC3=CN=CC=C3)C(F)(F)F
  • InChI=1S/C16H14F3N3OS/c1-24-14-7-10-4-6-22(13(10)8-12(14)16(17,18)19)15(23)21-11-3-2-5-20-9-11/h2-3,5,7-9H,4,6H2,1H3,(H,21,23)
  • Key:OQZOXHCRSXYSPM-UHFFFAOYSA-N

SB-221284 is a selective serotonin 5-HT2C and 5-HT2B receptor antagonist which is used in scientific research. [1] [2] [3]

Its affinities (Ki) are 2.2 to 2.5 nM for the serotonin 5-HT2C receptor, 2.5 to 12.6 nM for the serotonin 5-HT2B receptor, and 398 to 550 nM for the serotonin 5-HT2A receptor (where it is also an antagonist). [2] [4] [3] [5] The drug has 160- to 250-fold selectivity for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor. [1] [4] [3] It is said to have been the first serotonin 5-HT2C receptor ligand to show 100-fold selectivity over the serotonin 5-HT2A receptor. [6]

SB-221284 has shown anxiolytic-like effects in animals. [1] [5] [7] [8] Conversely, it has been said to be inactive in terms of antidepressant-like, antiobsessional-like, antipanic-like, and sedative effects. [1] [8] It also showed no proconvulsant or hyperphagic effects in animals, phenotypes that are notably observed with serotonin 5-HT2C receptor knockout. [3]

The preferential serotonin 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) and the serotonin reuptake inhibitor fluoxetine have been found to acutely reduce social interaction in rodents. [4] SB-221284 was found to reverse the acute decreases in social interaction produced by mCPP and fluoxetine. [4] The drug has also been found to block mCPP-induced hypolocomotion. [1] [5] [7] [9] Both SB-221284 and the selective serotonin 5-HT2C receptor antagonist SB-242084 have been found to enhance the nucleus accumbens dopamine release and hyperlocomotion induced by NMDA receptor antagonists like phencyclidine (PCP) and dizocilpine (MK-801). [9] Conversely, both drugs had no effect on locomotor activity or dopamine release in the nucleus accumbens by themselves. [9] However, another study reported that SB-221284 by itself did enhance locomotion. [4]

SB-221284 was first described in the scientific literature by 1996. [10] [3] It was researched by GlaxoSmithKline as a possible non-sedating anxiolytic and reached the preclinical research stage of development. [5] [11] [12] [3] However, it was found to be a potent inhibitor of a number of human cytochrome P450 enzymes (particularly CYP1A2), which precluded further development of the drug. [1] [12] [3] Other sources have stated that SB-221284 was not further developed due to "toxicity" [10] and that other drugs were pursued instead as SB-221284 was a "fairly weak" serotonin 5-HT2C receptor antagonist. [6]

Related Research Articles

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<i>meta</i>-Chlorophenylpiperazine Stimulant

meta-Chlorophenylpiperazine (mCPP) is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as "ecstasy" in Europe and the United States.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

<span class="mw-page-title-main">SB-242084</span> Chemical compound

SB-242084 is a selective antagonist of the serotonin 5-HT2C receptor which is used in scientific research.

<span class="mw-page-title-main">RS-102221</span> Chemical compound

RS-102221 is a drug developed by Hoffmann–La Roche, which was one of the first compounds discovered that acts as a potent and selective antagonist at the serotonin 5-HT2C receptor, with around 100× selectivity over the closely related 5-HT2A and 5-HT2B receptors. It has anxiolytic effects in animal studies, increases the effectiveness of SSRI antidepressants, and shows a complex interaction with cocaine, increasing some effects but decreasing others, reflecting a role for the 5-HT2C receptor in regulation of the dopamine signalling system in the brain.

<span class="mw-page-title-main">BW-723C86</span> Chemical compound

BW-723C86 is a tryptamine derivative drug which acts as a 5-HT2B receptor agonist. It has anxiolytic effects in animal studies, and is also used for investigating the function of the 5-HT2B receptor in a range of other tissues.

<span class="mw-page-title-main">Serotonin releasing agent</span> Class of compounds

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

<span class="mw-page-title-main">SB-215505</span> Chemical compound

SB-215505 is a drug which acts as a potent and selective antagonist at the serotonin 5-HT2B receptor, with good selectivity over the related 5-HT2A and 5-HT2C receptors. It is used in scientific research into the function of the 5-HT2 family of receptors, especially to study the role of 5-HT2B receptors in the heart, and to distinguish 5-HT2B-mediated responses from those produced by 5-HT2A or 5-HT2C.

<span class="mw-page-title-main">25B-NBOMe</span> Chemical compound

25B-NBOMe is a derivative of the phenethylamine psychedelic 2C-B, discovered in 2004 by Ralf Heim at the Free University of Berlin. It acts as a potent full agonist for the 5HT2A receptor. Duration of effects lasts about 3–10 hours, although the parent compound is rapidly cleared from the blood when used in the radiolabeled form in tracer doses. Recently, Custodio et al. (2019) evaluated the potential involvement of dysregulated dopaminergic system, neuroadaptation, and brain wave changes which may contribute to the rewarding and reinforcing properties of 25B-NBOMe in rodents.

<span class="mw-page-title-main">Serotonin antagonist and reuptake inhibitor</span> Class of drug

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

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

Pruvanserin is a selective 5-HT2A receptor antagonist which was under development by Eli Lilly and Company for the treatment of insomnia. It was in phase II clinical trials in 2008 but appears to have been discontinued as it is no longer in the company's development pipeline. In addition to its sleep-improving properties, pruvanserin has also been shown to have antidepressant, anxiolytic, and working memory-enhancing effects in animal studies.

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

1-(1-Naphthyl)piperazine (1-NP) is a drug which is a phenylpiperazine derivative. It acts as a non-selective, mixed serotonergic agent, exerting partial agonism at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptors, while antagonizing the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It has also been shown to possess high affinity for the 5-HT3, 5-HT5A, 5-HT6, and 5-HT7 receptors, and may bind to 5-HT4 and the SERT as well. In animals it produces effects including hyperphagia, hyperactivity, and anxiolysis, of which are all likely mediated predominantly or fully by blockade of the 5-HT2C receptor.

<span class="mw-page-title-main">SB-206553</span> Chemical compound

SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors.

5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.

<span class="mw-page-title-main">25CN-NBOH</span> Chemical compound

25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. It is a member of the NBOMe family of psychedelics.

<span class="mw-page-title-main">25N-NBOMe</span> Chemical compound

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<span class="mw-page-title-main">Locomotor activity</span> Behavioral measure in animals

Locomotor activity is a measure of animal behavior which is employed in scientific research.

<span class="mw-page-title-main">SB-228357</span> Chemical compound

SB-228357 is a drug which acts as a selective antagonist of the serotonin 5-HT2B and 5-HT2C receptors.

References

  1. 1 2 3 4 5 6 Lacivita E, Leopoldo M (2006). "Selective agents for serotonin2C (5-HT2C) receptor". Current Topics in Medicinal Chemistry. 6 (18): 1927–1970. doi:10.2174/156802606778522168. PMID   17017967. In particular, compounds 41 and 42 demonstrated 160- and 600-fold selectivity over 5- HT2A receptor, respectively. [...] Compounds 41-44 were evaluated for binding at 5-HT2B receptor and displayed modest selectivity. Compound 41 was found to have negligible affinity on a total of 57 different binding sites. 41 was also characterized as a competitive antagonist (pKB= 9.8) in the 5-HT-stimulated PI hydrolysis model of h-5-HT2C receptor activation in HEK-293 cells. Compounds 25, 39-43, 47-49 potently blocked the hypoactivity in rats produced by a standard dose of mCPP after oral administration (ID50 values around 1 mg/kg po). [...] Compounds 39, 41, 47, and 48 were further evaluated in two different models of anxiety in the rat (i.e. the Geller-Seifter Conflict Test and the Social Interaction Test) and were found to have significant anxiolytic activity with no evidence of sedative effects at doses (0.2-5 mg/ kg po) similar to those that antagonized mCPP-induced hypolocomotion. [...] The project aimed to the discovery of a selective 5-HT2C receptor antagonist at GSK evolved further [20] starting from compound 41 (SB-221284) and its methoxy analog 47 (Table 2). Compound 41 was found to be a potent inhibitor of a number of human cytochrome P450 enzymes (particularly the CYP1A2 isoform) and, therefore, further development was precluded.
  2. 1 2 Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, et al. (August 2004). "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 370 (2): 114–123. doi:10.1007/s00210-004-0951-4. PMID   15322733.
  3. 1 2 3 4 5 6 7 Bromidge SM, Dabbs S, Davies DT, Duckworth DM, Forbes IT, Ham P, et al. (May 1998). "Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines". Journal of Medicinal Chemistry. 41 (10): 1598–1612. doi:10.1021/jm970741j. PMID   9572885.
  4. 1 2 3 4 5 Bristow LJ, O'Connor D, Watts R, Duxon MS, Hutson PH (April 2000). "Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in the rat". Neuropharmacology. 39 (7): 1222–1236. doi:10.1016/s0028-3908(99)00191-4. PMID   10760364. SB 221284, an antagonist which has recently been disclosed and which has improved affinity and selectivity for 5-HT2C receptors compared to SB 200646A (Ki =2.5, 12.6 and 398 nM at 5-HT2C, 5-HT2B and 5-HT2A receptors, respectively; Bromidge et al., 1998).
  5. 1 2 3 4 Yang Y, An S, Liu Y, Guo XX, Gao L, Wei JF, et al. (2 January 2016). "Novel serotonin receptor 2 (5-HT2R) agonists and antagonists: a patent review (2004-2014)". Expert Opinion on Therapeutic Patents. 26 (1): 89–106. doi:10.1517/13543776.2016.1113257. PMID   26609882. SmithKline Beecham Pharmaceuticals has developed a number of useful anxiolytic agents targeting the 5-HT2C receptor, since the early 1990s. They revealed a number of bispyridyl ether compounds with selective 5-HT2A/2B/2C receptor antagonist activity (e.g., SB-242084 and SB-221284, compound 16 and 17, respectively, FIGURE 2), which exhibited significant anxiolytic activity and blocked the hypolocomotion in rats, centrally mediated by m-chlorophenylpiperazine (mCPP, compound 8, FIGURE 1), which is a hallucinogen also known as ecstasy with selective 5-HT2A/2C/2B agonist activity, an induce behavioral symptoms of anxiety in both animal models and humans.[29–31]
  6. 1 2 Blaney FE, Capelli AM, Tedesco G (20 January 2006). "7TM Models in Structure-based Drug Design". In Rognan D (ed.). Methods and Principles in Medicinal Chemistry. Wiley. pp. 205–239. doi:10.1002/3527608249.ch11. ISBN   978-3-527-31284-9. This led to the synthesis of SB-221284 (4) which was the first ligand to show over 100-fold selectivity for 5-HT2C [21]. The compound was still fairly weak as an antagonist so further elaboration was necessary.
  7. 1 2 Bromidge SM, Dabbs S, Davies DT, Davies S, Duckworth DM, Forbes IT, et al. (March 2000). "Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent". Journal of Medicinal Chemistry. 43 (6): 1123–1134. doi:10.1021/jm990388c. PMID   10737744. Subsequently, we developed a number of selective 5-HT2C/B receptor antagonists, such as 1 (SB206553) and 2 (SB-221284), which block the centrally mediated mCPP-induced hypolocomotion in rats. These compounds also exhibited significant anxiolytic activity in several different animal models, lending strong support to our original hypothesis.4-6
  8. 1 2 Jenck F, Bös M, Wichmann J, Stadler H, Martin JR, Moreau JL (October 1998). "The role of 5-HT2C receptors in affective disorders". Expert Opinion on Investigational Drugs. 7 (10): 1587–1599. doi:10.1517/13543784.7.10.1587. PMID   15991903. In contrast, 5-HT2C receptor antagonists such as SB-200646A or SB-221284 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of antidepressant, anti-OCD and antipanic activity.
  9. 1 2 3 Hutson PH, Barton CL, Jay M, Blurton P, Burkamp F, Clarkson R, et al. (September 2000). "Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies". Neuropharmacology. 39 (12): 2318–2328. doi:10.1016/s0028-3908(00)00089-7. PMID   10974315.
  10. 1 2 Steele P (1996). "Meeting Highlights: 7th Symposium on Medicinal Chemistry in Eastern England". Expert Opinion on Investigational Drugs. 5 (6): 787–790. doi:10.1517/13543784.5.6.787. ISSN   1354-3784. The result was the optimised indoline SB-221284 (4), with 140-fold 5-HT2c selectivity, pKi = 8.6, ID50 = 1.5 mg/kg, and a minimum effective dose of 1 mg/kg in the Geller-Seifter test. SB-221284 is no longer in development because of compound-related toxicity problems, but a suitable analogue, not identified, has been located as a replacement.
  11. ↑ Griebel G (1997). "Serotonergic drugs in animal models of anxiety: an update" (PDF). Serotonin ID Res. Alert. 2: 251–257.
  12. 1 2 Pauli I, Timmers LF, Caceres RA, Soares MB, de Azevedo WF (December 2008). "In silico and in vitro: identifying new drugs". Current Drug Targets. 9 (12): 1054–1061. doi:10.2174/138945008786949397. PMID   19128215. Compound SB 221284 was selected on the basis of its overall biological profile for further evaluation as a potential, novel, nonsedating anxiolytic agent. Unfortunately, these compounds were found to be potent inhibitors of several human cytochrome P450 enzymes which precluded their further development [63].
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