Tropisetron

Tropisetron (ICS 205-930) is a synthetic, indole-based small molecule, an ester of indole-3-carboxylic acid and tropine that joins an indole ring to a tropane group (Papke et al., 2005). It is a selective 5-HT3 receptor antagonist and also a potent partial agonist at alpha7 nicotinic acetylcholine receptors (Macor et al., 2001).

PubChem lists the hydrochloride salt separately (CID 656664, C₁₇H₂₁ClN₂O₂, 320.8 g/mol).

Published work on tropisetron falls into six areas; each summary names its model. Most evidence is from receptor assays and animal studies; the human studies here are small schizophrenia trials.

5-HT3 receptor antagonism

In 1985, Richardson and colleagues reported a new class of drugs that selectively block serotonin M-receptors on peripheral neurons, some among the most potent drugs yet reported, and used them to identify three M-receptor subtypes (Richardson et al., 1985). PubMed indexes tropisetron among that paper's compounds. A 1986 nomenclature proposal co-authored by Richardson named the receptor group that broadly covers M-receptors 5-HT3 (Bradley et al., 1986). Models: peripheral neurons and isolated tissues.

Partial agonism at the alpha7 nicotinic receptor

Macor and colleagues reported that tropisetron is a potent and selective alpha7 partial agonist, whereas ondansetron, another 5-HT3 antagonist, lacked high affinity for this receptor (Macor et al., 2001). In oocytes expressing human nicotinic receptors, the simpler tropane and tropinone kept alpha7-selective agonist activity, and the indole group appeared to set tropisetron's potency as an alpha7 agonist and as an alpha3beta4 inhibitor (Papke et al., 2005).

A later oocyte study measured EC50 values near 2.4 µM at alpha7 and 1.5 µM at alpha7beta2 receptors, and sustained 10 and 30 nM tropisetron enhanced acetylcholine-evoked currents, a priming or co-agonist effect (Callahan et al., 2017). Models: receptor assays and oocytes.

Sensory gating and memory in animal models

DBA/2 mice naturally show deficient gating of the P20-N40 auditory evoked potential, a rodent analog of the P50 deficit in schizophrenia. Tropisetron had a normalizing effect on this deficit, and the partially selective alpha7 antagonist methyllycaconitine blocked it (Hashimoto et al., 2005).

In Wistar rats, tropisetron lessened the prepulse inhibition deficit caused by apomorphine, an effect methyllycaconitine antagonized, but not the deficit caused by phencyclidine (Kohnomi et al., 2010). It also raised novel object recognition in young and aged rats and produced a 17% rise from baseline in delayed match-to-sample accuracy at long delays in aged rhesus monkeys (Callahan et al., 2017). Models: mice, rats and monkeys.

Clinical studies in schizophrenia

In an initial proof-of-principle study in people with schizophrenia, tropisetron given once significantly increased P50 inhibition (Koike et al., 2005). In an 8-week randomized, double-blind, placebo-controlled trial in 40 people with chronic schizophrenia on risperidone, P50 ratios fell in non-smokers on tropisetron but not placebo; cognitive battery (CANTAB) scores did not differ between groups, though a within-group analysis found higher sustained visual attention scores on tropisetron, and PANSS scores did not change (Shiina et al., 2010).

A 10-day double-blind trial in 40 non-smokers compared three daily amounts with placebo: all three raised overall cognitive battery (RBANS) scores, P50 deficits lessened, and two participants in the highest-amount group withdrew because of adverse effects (Zhang et al., 2012).

A one-day version of that design reported higher RBANS scores and smaller P50 ratios in some groups (Xia et al., 2020). In an 8-week add-on trial in 40 people with chronic, stable schizophrenia, tropisetron produced larger falls than placebo in PANSS total, negative and general psychopathology scores, but not positive scores (Noroozian et al., 2013). Models: small human trials.

Inflammation and neuroinflammation

In human and Jurkat T cells, tropisetron inhibited T cell receptor-driven activation, IL-2 production and NFAT and AP-1 activity, and tests with a constitutively active calcineurin pointed to this phosphatase as a main target, probably independent of serotonin receptors (de la Vega et al., 2005). In mice with dextran sulfate sodium colitis, tropisetron lessened colitis, methyllycaconitine weakened that effect, and alpha7 stimulation lowered colon IL-6, interferon-γ and macrophage infiltration (Tasaka et al., 2015).

In rats given hippocampal amyloid-beta 1-42, tropisetron delivered into the brain ventricles lowered hippocampal TNF-α, COX-2, iNOS, NF-κB and calcineurin activity and reversed the cognitive deficit; a 5-HT3 agonist fully reversed its cognitive and anti-apoptotic effects but only partly its anti-inflammatory effects (Rahimian et al., 2013). Models: human T cells, mice and rats.

Amyloid precursor protein and Alzheimer's models

A screen of a clinical compound library in CHO cells expressing human amyloid precursor protein (APP) picked out tropisetron because it raised soluble APP-alpha (sAPPα). In neurons and mice of the J20 (PDAPP) transgenic line it raised the sAPPα to amyloid-beta 1-42 ratio, and the mice showed better spatial and working memory in pre-plaque and late plaque phases.

The authors also reported that it binds the APP ectodomain (Spilman et al., 2014). The amyloid-beta rat study above is a second, independent model (Rahimian et al., 2013). This Alzheimer's evidence is from cell and animal models only. Models: CHO cells, J20 mice and neurons, and rats.