Design And Synthesis Of The Novel Serotonin (5-HT)_1A Receptor Ligands

5-HT is an important neurotransmitter. 5-HT receptors (5-HTRs) play significant functions in most of human nervous activities such as cognition, affection and are crucial medicinal targets. Among 5-HTRs, the 5-HT1A receptor (5-HT1AR) subtype is the best studied. The research of 5-HT1A receptor ligands (5-HT1ARL) is beneficial to treat anxiety, depression, pain, etc. 5-HT1ARL has great drug investigation prospect. Now, one hand, the research of the high selectivity and affinity 5-HT1ARL is paid close attention to; the other hand, the design and synthesis of multi-target-directed ligands (MTDLs) is a significant research aspect. Along with the magnanimous new types of compounds, the 5-HT1ARL drug investigation prospect will be luciferous. The purpose and content of this research topic is to design and synthesize novel 5-HT1AR ligands of multi-target-directed effect and intellectual property rights, looking for new category drug to treat pain, depression, anxiety.The paper included the several parts of research works illustrated below:1. Based on comprehensive analysis of the 5-HT1A receptor ligands reported by literatures and the preliminary test exploration, piperidine-4-methanamine was chosen as the lead structure. On the basis of reported findings of piperidine-4-methanamine derivatives structure-activity relationship (SAR) and its drug property, through functional group substitution and bioisostere substitution, a new type of 5-HT1ARL was designed and synthesized.2. 27 new compounds were synthesized; all compounds are beyond the literatures.3. The structure of all the compounds was identified by 1H-NMR, some of them were further validated by MS.4. 11 compounds were preliminarily monitered 5-HT1AR affinity activity by making use of competitive-binding assay with radioactive 5-HT1AR ligand in rat hippocampus. Among them, YL-02 and YL-11 displayed nearly as good affinity activity as that of the positive control 8-OH-DPAT; In the mouse hot plate test, after administration, the analgesic effect of the compounds YL-03,YL-06,YL-07,YL-08 and YL-11 displayed progressive tendency along with the time. It consistented with the feature of the piperidine-4-methanamine derivatives analgesic effect; In the acetic acid writhing test, YL-08, YL-09, YL-26 and YL-27 showed rather noticeable analgesic effect.5. Based on the results of preliminary screens, the structure-activity relationship is as follows:1) when the substituent group on the N-site of the piperidine ring was replaced benzoyl by benzyl, affinity of the compounds remained quite a lot. Thus the benzoyl group of lead compound may not be necessary for the affinity activity, and it is possible to design and synthesize novel 5-HT1ARL to breakthrough the patent protection of lead compound and obtain own intellectual properties;2) The connection carbon-bond number of aromatic ring on the amino group of the piperidine-4-methanamine is critical to the receptor affinity activity. Maybe as the SAR research results of lead compound showed, one carbon bond is reasonable;3) While aromatic ring on the substitutive amino group such as phenyl, pyrimidinyl, pyridyl or larger group like phthalimide seems to be trivial to the affinity activity; meanwhile, in the acetic acid writhing test at the dose of 5.0mg/kg ip, besides YL-09, YL-08, YL-26 and YL-27 also displayed rather conspicuous analgesic effect. It illustrated that the aromatic ring with nitrogen was not necessary in this series of compounds, and that large group on the aromatic group may increase analgesic effect.4) When the other substituent of the 4-site of the piperidine ring is replaced fluoro by hydroxyl, its receptor affinity activity remains.5) In the mouse hot plate test, the analgesic effect of the compounds YL-03, YL-06, YL-07, YL-08 and YL-11 displayed progressive tendency along with the time. It showed that the novel 5-HT1ARL similar as the piperidine-4-methanamine derivatives can keep the same analgesic effect, and that its analgesic activity increases along with the time in a mirror-inverse effect compared to that of the opiate and may not induce tolerance.In conclusion, we have designed and synthesized 27 new compounds. The results of the biological activity evaluation suggested that compound YL-02 and YL-11 have displayed good receptor affinity activity, and YL-08, YL-09, YL-26 and YL-27 have showed rather noticeable analgesic effect. They are of privileged structure and significant to research deserving a further step.