Design, Synthesis And Activity Study Of Non-imidazole H₃ Receptor Antagonists

Histamine H₃ receptor is a new histamine receptor sub lype,which belongs to the superfamily of G-protein-coupled receptors.It regulates the synthesis and release of histamine as well as many other neurotransmitters,therefore.H₃ receptor antagonists are proposed to have therapeutic applications in narcolepsy,obesity,hypokinesia. cognitive disorders,attention deficit hyperactivity,disorder(ADHD),etc.H₃ receptor antagonists can be divided into two classes based on their differences in chemical structures—imidazole and non-imidazole.Since antagonists bearing imidazole groups have certain fatal disadvantages,such as inability to penetrate the brain blood barrier and inhibition of cytochrome P₄₅₀ enzymes,more and more attentions were attached to the research and development of the non-imidazole H₃ receptor antagonists during the past few years.Based on the analysis of the structure and activity relationship of the reported compounds,two series of non-imidazole H₃ receptor antagonists bearing indole moiety have been designed:First,1-aminomethyl phenyloxyalkyl substituted indole derivativesâ… -1～Ⅰ-14 were designed and synthesized based on the lead compound 1-53,whose phenol alkylamine segment was replaced by benzyl amine segment,an effective structural moeity proved by previous work,which was then linked to indole by ether chain of different length.The second series of 1,3- substituted indole derivatives,based on the lead compound 2-9. including three subtypes:(1).1-amine alkyl -3-amide alkyl-substituted indole derivativesâ…¡-1～Ⅱ-8 were synthesized according to the bioisosterism principle by replacing the benzofuran structure with indole ring,which then linked with amine on the 1 position as a basic part,and amide possessing a H-bond acceptor on the 3 position;(2).1,3-diamine alkyl indole derivativesâ…¡-9～Ⅱ-16 were synthesized by reduction of the above amide derivatives.(3).1-aminomethyl phenyloxyalkyl -3-amide alkyl indole derivativesâ…¡-17～Ⅱ-23 were designed and synthesized according to combination principles by adding amide to the 3 position of indole ring, in order to increase the affinity to H₃ receptor.Thirty seven novel compounds have been synthesized starting from indole,and confirmed by ¹H-NMR and MS.Ten compounds have displaved as potential H₃ receptor antagonist in in-vitro experiment.The activity of the other compounds are currently under investigation.