The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 μM. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 μM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP+. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 μM; as well as significant NMDAr antagonists with compound 5 showing the best activity of 88.3% at 10 μM. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC50 = 1.70 μM). Generally, the compounds were about 3–52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds' possible putative binding modes within the MAO-B enzyme cavity were assessed in silico. Display omitted •In silico studies guided the design of twelve new polycyclic cage compounds.•All compounds showed significant neuroprotection between 31% and 61% at 1 μM.•The compounds have VGCC and NMDAr Ca2+ regulatory potential similar to or better than NGP1-01.•In vitro and in-silico studies suggest the compounds to be reversible MAO-B inhibitors.•The inclusion of the propargylamine led to multi-mechanistic neuroprotective agents.