5-HT3-receptor antagonists

Aapro MS 5-HT3 receptor antagonists an overview of their present status and future potential in cancer therapy-induced emesis. Drugs 42 551-568, 1991... 

Olivier, B, van Wijngaarden, I and Soudijn, W (2000) 5-HT3-receptor antagonists and anxiety a preclinical and clinical view. Eur. Neuropsychopharmacol. 10 77-95. 

Droperidol or a 5-HT3 receptor antagonist should be administered at the end of surgery to patients at high risk for developing postoperative nausea and vomiting. 

Evaluate 5-HT3 receptor antagonists (alosetron) for relief of abdominal pain and fecal incontinence. 

There are three main drug targets that are antagonized to prevent or treat acute and delayed CINV 5-HT3 receptors, dopamine type 2 receptors (D2), and NK-1 receptors. 5-HT3-receptor antagonists are the most effective agents for preventing... 

Ondansetron A 5-HT3 receptor antagonist that may have a nootropic effect. 

In connection with a study of potential serotonin receptor antagonists, some decahydrocyclazin-6-ones and -6-ols have been synthesized from acyclic precursors <1992SC3115> (Scheme 115), but those esters derived from the latter (both epimers) which have been tested to date as potential 5-HT3 receptor antagonists have shown little biological activity <1993EJM869>. 

An important advance in this field has been made by the discovery of selective serotonin (5-HT3) receptor antagonists that are effective inhibitors of cytotoxic drug-induced emesis in laboratory animals. The new agents have been found to be free of the undesirable side-effects associated with dopaminergic blockade and have shown significant protection from emesis in early clinical trials. 

Parallel with the developments in the benzamide area, progress was also made in several nonbenzamide series of compounds. MDL 72222 (26) [20], atropine ester of 3,5-dichlorobenzoic acid, was the first selective 5-HT3 receptor antagonist and a potent antagonist of cisplatin-induced emesis in the ferret [21]. ICS 205-930 (27) [22,23 ], the tropine ester of 3-indolecarboxylic acid, exhibited similar pharmacological and antiemetic profiles. 

Compounds (29) and (30) were found to be comparable in potency to (27) as 5-HT3 receptor antagonists analogue (31) was substantially less potent. The loss of activity found with (31) was attributed to steric interactions of the A-methyl group and amide NH as well as the ethylene bridge of the tropane... 

In the 1-methylindazole series the synthesis of a potent 5-HT3 receptor antagonist BRL-43694, granisetron, (32) has also been reported [25, 26]. 

Further divergence from classical benzamide structure is represented by the synthesis of ondansetron (GRF 38032F, (33)), a potent 5-HT3 receptor antagonist where the basic nitrogen atom is part of an imidazole ring and the aromatic ring is part of tetrahydrocarbazolone ring system [27],... 

Greenshaw AJ. (1993). Behavioural pharmacology of 5-HT3 receptor antagonists a critical update on therapeutic potential. Trends Pharmacol Sci. 14(7) 265-70. 

Greenshaw AJ, Silverstone PH. (1997). The non-antiemetic uses of serotonin 5-HT3 receptor antagonists. Clinical pharmacology and therapeutic applications. Drugs. 53(1) 20-39. 

Martin P, Gozlan H, Puech AJ. (1992). 5-HT3 receptor antagonists reverse helpless behaviour in rats. Eur J Pharmacol. 212(1) 73-78. 

Many in vitro assay systems have been developed for studying substances which interact with the 5-HT3 receptor. Outlined in the next section are those most commonly used to assess 5-HT3 receptor antagonist activity. This is followed by a section on the in vivo tests to assess 5-HT3 receptor activity,... 

A second assay which has been used extensively in the characterization of 5-HT3 receptors is the rabbit isolated heart. Both the sympathetic and parasympathetic inputs to the rabbit heart can be influenced by stimulation of 5-HT3 receptors this preparation is usually performed in the presence of atropine to block parasympathetic effects [12]. Under these conditions, 5-HT and other 5-HT3 receptor agonists exert positive effects on rate and contractile force. Selective 5-HT3 receptor antagonists such as MDL 72222 [6], ICS 205-930 [3] and ondansetron [7] block the agonist effects in a concentration-related manner. 

Richardson and colleagues [3] identified a simple in vivo assay for the 5-HT3 receptor in man. They showed that the application of 5-HT to the exposed base of a blister evokes a pain and a wheal and flare response. These can be blocked by 5-HT3 receptor antagonists. Obviously one needs willing volunteers for such studies and suitable safety data must be available, but this is a useful model for assessing 5-HT3 receptor antagonist activity in man. 

Indications for several therapeutic uses of 5-HT3 receptor antagonists have come from behavioural studies. These compounds have little or no ef-... 

The disinhibitory effects of 5-HT3 receptor antagonists are now well documented [29, 30]. These compounds act to restore normal behaviour to animals in conditions which are mildly aversive, such as a novel brightly lit test area. Such effects may be predictive of anxiolytic activity. An example of such disinhibition is the effect of ondansetron in the rat social interaction test in which the level of interaction between two rats is measured under certain defined conditions [29]. In non-aversive conditions this type of behaviour is quite marked, but it is suppressed in novel highly illuminated conditions. Ondansetron overcomes this suppression, as do known anxiolytics such as diazepam. 

Mesolimbic dopamine pathways are thought to be involved in the rewarding effects of drugs of abuse and an imbalance of this pathway is thought to be causal in psychoses. Several studies have revealed that 5-HT3 receptor antagonists can correct such imbalances. Thus, ondansetron inhibits the behavioural hyperactivity resulting from direct stimulation of this... 

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