Previous research on the possible target for treatment of neurodegenerative diseases such as Alzheimer’s has indicated the value of studying selective agonist to nicotinic acetylcholine receptors (nAChRs). Following this route, we made a strong effort in studying the ligand binding to nAChRs, especially the 7 subtype. We have characterized the central pyrimidine ring and the 2-(Di-picolyl) substituted at the 4 position of the pyrimidine as important motifs for the selective agonistic activity. To further explore the characteristics of crucial motif, we synthesized 7 intermediate and 8 final compounds accordingly, each rationally designed to confer a unique chemical property. The analogue library was tested in HEK cells transfected with cDNAs encoded for α7- nAChR, α4β2-nAChR, and a serotonin receptor (5-HT 3A) along with a florescent reporter. We observed the symmetry in the 2-(Di-picolyl) motif, the hydrophilicity of the second position, as well as the presence of the amino group in the second position are crucial for agonistic activity. Final compounds were rationally designed following these observations and one leading compound was shown to be able to cross the blood-brain barrier. In conclusion, the structure of the compound has determining effect on the agonistic activity, efficacy as well as its ability to traverse the physiological blood-brain barrier. This structure-activity information is extremely valuable and should be considered in future ligand design.