From Serotonin to Tegaserod

The activities of the indole carbazimidamide derivatives 5 at the 5-HT4 receptor were measured in vitro using the field-stimulated LMMP-GPI preparation (Table 1) followed by in vivo investigations applying the gastric emptying and intestinal transit models in the guinea-pig and rat. 

We first tried to optimize the environment around the charged guanidine using 5a (R5 = OH) as a reference compound for structure-activity relationship (SAR) determination. 

Among aliphatic substituents, the pentyl side chain was found to be optimal for both in vitro potency and efficacy. Derivative 5b (R5 = OH, R9 = M-pentyl) is a full agonist in the LMMP-GPI model (90% of the maximum efficacy of serotonin  

However, the findings from modification of the aminoguanidine moiety, which resulted in decreased potencies, were consistent with the hypothesis of a dual-type binding mode for this head group. On the other hand, replacing one nitrogen of the guanidine with a carbon or a sulfur retained activity. 

Increasing the size of the ether substituent (5i) led to a further increase in potency and efficacy in vitro. However, this improvement in vitro, which might be accounted for by secondary lipophilic interactions, did not improve efficacy in vivo. Substitution at the 5-position of the indole nucleus by larger polar or lipophilic substituents (5j) abolished activity in vitro. 

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