Extracellular calcium flow through neuronal voltage-gated Ca2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The Ca2.2 channel is composed of a pore-forming α subunit (Caα) that is engaged in protein-protein interactions with auxiliary α/δ and β subunits. The high-affinity Ca2.2α⋅Caβ protein-protein interaction is essential for proper trafficking of Ca2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the Ca2.2α⋅Caβ protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of Ca2.2α Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and Caβ Arg-307. In cells, compounds decreased trafficking of Ca2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.