Amantamide B (<b>1</b>) is a new linear nonapeptide analogue of the cyanobacterial natural product amantamide A (<b>2</b>), and both have methyl ester and butanamide termini. These compounds were discovered in this study from the organic extract of a tropical marine filamentous cyanobacterium, <i>Oscillatoria</i> sp., collected around the Paracel Islands in the South China Sea. The use of LC-MS/MS molecular networking for sample prioritization and as an analytical dereplication tool facilitated the targeted isolation of <b>1</b> and <b>2</b>. These molecules were characterized by spectroscopy and spectrometry, and configurational assignments were determined using chemical degradation and chiral-phase HPLC analysis. Compounds <b>1</b> and <b>2</b> modulated spontaneous calcium oscillations without notable cytotoxicity at 10 μM in short duration in vitro testing on primary cultured neocortical neurons, a model system that evaluates neuronal excitability and/or the potential activity on Ca<sup>2+</sup> signaling. Both molecules were also found to be moderately cytotoxic in longer duration bioassays, with in vitro IC<sub>50</sub> values of 1-10 μM against CCRF-CEM human T lymphoblastoid cells and U937 human histiocytic lymphoma cells. These formerly undiscovered bioactivities of known compound <b>2</b> expand upon its previously reported function as a selective CXCR7 agonist among 168 GPCR targets.