4-Amino-piperidine Library: Studies On Synthesis And Activities Of Blockers For N-type Calcium Channel

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage or both. Many diseases have pain as an important symptom. The opioid agents such as morphine and buprenorphine hydrochloride are widely used in clinic for mild or severe pain. Since addictive, hypotension and sedation are very common side effects of these drugs, drug discovery efforts in the past focused on novel analgesic agents with no adverse events and new action mechanism.Recently, there are great progresses in the researches of novel analgesic drugs targeted N-type calcium channel. And w-conotoxin MVIIA (Ziconotide? is one of the most potential compounds. Since several of key amino acids responsible for the binding of the toxin to the channel pores have been determined to be Argl0, Leull and TyrlS, we designed a small library with 4-amino-piperidine template to fit the conformation of the possible pharmacophoric groups.The paper includes the several works illustrated below:1. We choose N-type calcium channel as the target of new type of analgesic drugs. A non-peptidyl small molecule library was designed with three substitutions on the template. The building blocks consist of aldehydes and amines which are mimetics of the side chain of the key binding amino acids of Ziconotide.2. Two liquid phase synthetic routes were employed here for the synthesis of the different structural of 4-amino-piperidine compounds by which the common intermediates can be make good use of. All of the reaction conditions are moderate, timesaving and easy to workup which is suitable for the large scale parallel synthesis. The results showed that both of these synthetic routes are effective and convenient for the generation of molecule diversity. A small library containing 126 compounds of 4-amino-piperidine analogues was generated for the screening.33. HNMR and MS (ESI) were used to identify the structure of the library in order to make sure of the feasibility and reliability of the synthetic routes. The quality of the library was corroborated by the analysis of 13 compounds with HPLC technique, the result shows that the purity of the compounds is above 85%.4. 96 of library compounds were initially screened using the mouse acetic acid writhing test. 29 compounds were found to have obvious pain relief effects. 9 compounds were identified to have approximate actives to the control compounds (ZC1 and ZC2).5. Some of the active compounds were then screened using in vitro u receptor binding model. The results were used to assess the affinities of the library compounds to the u opioid receptors. The result shows that the binding affinities of activity compounds to the i opioid receptor are low. It is suggested that the molecular mechanisms underlying its analgesic action maybe include Ntype calcium channel activation.6. Based on the screening data, the structure-activity relationship analysis is as follows:i) The template of4-amino-piperidine can be modified.ii) The dimethylamino-benzyl is a good substitution of the piperidine nitrogen ring for resulting in biological activity.iii) The substitution of nitrogen of the amine group plays a key role to the activities. The para-substituted benzaldehyde derivatives are more preferred for analgesic effect than the ortho- and meta-substituted analogues.iv) The space selectivity effect of the substitutions of amine group has little influence to the activities. It is suggested that size limit of binding site of the receptor to the ligand is more tolerance. The further pharmacophore perception can lead us to design new chemical entities with novel structural characters and better activity.Conclusion: We have constructed a combinatorial library which is contained 126 new compounds. The compounds were screened by the mouse acetic acid writhing test. Some of the active compounds were then screened using in vitro u receptor binding4model. The results suggested that the molecular mechanisms underlying its analgesi...