Natural product total synthesis enables gain of function through deep-seated modification of structure. Synthetic difficulty can, however, obstruct meaningful optimization campaigns. To simplify access, the complexity of the target (TGT) can be lowered—a strategy described within function-oriented synthesis. Alternatively, the chemical space immediately surrounding the TGT can be searched for analogs of equal or greater complexity that also simplify access. This strategy—dynamic retrosynthetic analysis—maintains most physicochemical properties of the TGT (locus in chemical space) but opens new synthetic paths unavailable to the natural product itself and can provide functional advantage. Here we experimentally interrogate these ideas by generation of two parallel series of picrotoxinin (PXN) analogs to identify leads with ligand-gated ion channel (LGIC) selectivity. One series derives from PXN via semi-synthesis, and the other from 5MePXN via total synthesis. Methylation at C5 decreases potency against vertebrate ion channels (GABAa receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (RDL receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. The C5 methyl also stabilizes the scaffold substantially against irreversible C15 solvolysis by destabilizing an intermediate twist-boat conformer, which returns to 5MePXN instead of progressing to degradant. These discoveries are made possible by the lower synthetic burden of 5MePXN and are illuminated by the parallel analog series, which allows unambiguous identification of the role of the synthetically simplifying C5 methyl. Rapid access to functionally-privileged analogs by TGT point mutation underscores the value of dynamic retrosynthetic analysis as a problem-solving heuristic.