CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Abstract

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT 3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT 3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT 3 receptor (K i approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the K i value for the 5-HT 3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT 3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT There is a lack of effective current treatment for diarrheapredominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT 3 receptor is thought to be implicated in the pathophysiology. Because 5-HT 3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT 3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.

Effects of Dexmedetomidine on Rats with Functional Chronic Visceral Pain Based on Protein Expressions in the Extracellular Signal-Regulated Kinase 1/Cyclic Adenosine Monophosphate Response Element-Binding Protein Signaling Pathway

“…The pathogenesis of such disease is complicated and its molecular mechanism has not yet been fully elucidated. Due to the lack of clinically effective drugs, the current treatment of this disease is mainly dominated by controlling the progression of clinical symptoms such as abdominal pain and diarrhea in patients [15] . With the development of minimally invasive surgery and digestive endoscopy diagnosis and treatment technology, laparoscopy and digestive endoscopy can be used to diagnose and treat many digestive tract diseases or even tumors, so the effective intervention for visceral noxious stimulation and visceral pain is also one of the issues that need more attention [16] .…”

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

“…In fact, the 5-HT 3 R partial agonist prevented the complete inhibition of the receptor, reducing the probability of constipation and ischemic colitis. CSTI-300 was shown to be a high-affinity 5-HT 3 R partial agonist with a good dose-dependent efficacy in a rodent model, representing a potential promising treatment mostly for patients with diarrhea-predominant CS, with less constipation than alosetron [ 83 ].…”

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

“…An example involves the functional neural 5-HT 3 receptors present along the length of the mouse, rat and guinea pig intestinal tracts that show differences in agonist efficacies between species and in separate regions of the tissue [ 182 , 183 ]. Interest has been generated in partial agonists as potential therapeutic agents and CSTI-300 is one such compound that has recently been characterized [ 184 ].…”

“…Therefore, the ligands can be classified by the site they bind: 1. competitive antagonists (e.g., ondansetron); 2. non-competitive antagonists (e.g., picrotoxin) acting via locations other than the orthosteric binding site; 3. dual acting antagonists (e.g., palonosetron [ 206 , 207 ]), which bind at orthosteric or transmembrane sites although structural studies indicate palonosetron only binds at the orthosteric site [ 145 ]; and 4. allosteric modulators that bind at sites distinct from the orthosteric site such as the interface of the extracellular and transmembrane domains [ 15 , 19 , 141 , 142 , 143 , 145 , 150 , 151 ] ( Figure 2 A). Importantly from an experimental and potentially clinical view (see below), ligands can have different potencies at 5-HT 3 A versus 5-HT 3 AB receptors [ 89 , 184 , 185 , 208 , 209 , 210 ]. For instance, the agonist m-CPBG can bind at all five interfaces of 5-HT 3 AB distinguishing it from 5-HT, which only binds at the orthosteric binding site at the A+A- interface within the 5-HT 3 AB receptor enabling allosteric modulation [ 208 ].…”

“…Since 5-HT levels rise in diarrhea conditions, a new rationale involving use of 5-HT 3 receptor partial agonists has been suggested. Selective partial 5-HT 3 receptor agonists (e.g., CSTI-300) compete with high levels of endogenous 5-HT but do not completely inhibit the receptor and pre-clinical studies in animal models did not evoke constipation or emesis [ 184 ]. Therapies involving CSTI-300 or its analogs are also likely to be beneficial for patients suffering chronic diarrhea and increased circulating 5-HT such as occurs in carcinoid syndrome or diabetes induced diarrhea currently treated with 5-HT 3 receptor antagonists [ 184 , 223 , 224 , 225 ].…”