Design, Synthesis And Study Of H₃ Receptor Antagonistic/Agonistic Activity Of Indole (Pyridine) Alkylamine Derivatives

The histamine H3 receptor (H3R) is a G-protein-coupled receptor (GPCR), which predominantly expressed in the central nervous system (CNS). It is a presynaptic autoreceptor regulating the synthesis and release of histamine. It is also known as a heteroreceptor in the regulation of releasing several other important neurotransmitters, such as acetylcholine, dopamine, noradrenaline and serotonin. H3 receptor antagonists/inverse agonists have been proved to enhance the release of neurotransmitters both in vitro and in vivo, which could be a useful therapeutic strategy for CNS disorders, for instance, Alzheimer's disease, epilepsy, attention deficit hyperactivity disorder (ADHD) and so on. H3 receptor agonists are useful for the areas of ischemic arrhythmias, migraine, and asthma. Based on sufficient analysis and detailed study on the structure-activity relationships of H3 receptor antagonists and agonists, two series of H3 receptor antagonists and one series of H3 receptor agonists were carefully designed.(1) A series of N-banzylamine-indole-3-amide derivatives were designed by employing indole group as the central core and benzylamine fragment as the amino region. Both were connected by different linkers based on the rule of bioisosterism principle. Accordingly,24 novel N-banzylamine-indole-3-amide ones were synthesized, and confirmed by]H NMR and MS.(2) It is well known that 2-alkylaminebenzofuran derivatives were described as potent H3 antagonists. Here we opened the benzofuran ring to phenylether alkyl group and designed a series of N-3-pyridine-benzamide derivatives. In this series,21 novel compounds were obtained.All the 45 compounds were tested in vitro for their H3 receptor activity and the results showed that they were potent H3 receptor antagonists. The structure-activity relationship study revealed that the potency of analogs could be enhenced, when morpholine was selected as the amino group and alkylamine as the linker. Among them, compoundsⅠ-13,Ⅰ-22,Ⅰ-23,Ⅰ-23,Ⅲ-14 andⅢ-30 showed similar affinities compared with positive control.(3) In our previous work, a dibasic compound ZEL-H16 was discoverd as a potent H3 agonist. By introducing an amine/amide side chain in position 3, a series of 3-propylamine-l-amine (amide) indole derivatives were designed. Accordingly,23 novel 3-propylamine-l-amine (amide) indole ones were designed, synthesized, and confirmed by 1H NMR and MS. The result of H3 receptor activity test showed that they were potent H3 receptor agonists or partial agonists.Ⅱ-15 andⅡ-16, with excellent EC50 values of 0.14 and 0.13nM respectively, were the most active compounds and exhibited more than 100 fold increasing in potency compared with histamine.