Pharmacokinetic and pharmacological characterization of novel agmatine-based antihyperalgesic compounds.

Chronic pain remains a major burden to patients globally. The use of current established analgesics can be limited because of side effects. Agmatine, a nonopioid endogenous amine, reduces hyperalgesia in chronic pain. However, a relatively short plasma half-life and potentially moderate distribution across biological barriers may limit use. We developed a line of agmatine-based novel antihyperalgesic compounds with increased lipophilicity to improve biodistribution to the central nervous system (CNS). Through the present study, we compared 4 agmatine-based compounds for their initial pharmacological outcomes in vivo in models of thermal and tactile hypersensitivity, and we characterized their pharmacokinetic profiles and distribution to the CNS. To determine pharmacokinetic parameters, strategically substituted agmatines (SSAs) SSA1-4 were administered intravenously or orally, and plasma concentrations were assessed using high-performance liquid chromatography-mass spectrometry/mass spectrometry. To determine the in vivo pharmacological effects, agmatine or SSA1-4 were administered intrathecally, systemically, or orally, and the inhibition of N-methyl-d-aspartate-evoked nociceptive responses or complete Freund adjuvant-induced tactile hypersensitivity was determined. Agmatine and SSA1-4 inhibited N-methyl-d-aspartate-evoked nociceptive behaviors and thermal hyperalgesia following intrathecal administration. Distribution and elimination half-life were comparable to or increased relative to the parent compound, although oral bioavailability (SSA3 and SSA4) became limited by solubility. Both SSA3 and SSA4 effectively crossed the CNS barriers, and SSA4 resulted in increased CNS agmatine concentrations. These results suggest that the SSAs induce similar pharmacological outcomes compared with agmatine, with improved CNS distribution and plasma exposure. Agmatine-based compounds may be effective alternative antihyperalgesic agents for the treatment of pain. SIGNIFICANCE STATEMENT: Four new chemical entities, based on the agmatine structure, demonstrate comparable or improved pharmacokinetic parameters and pharmacological responses relative to agmatine. Agmatine-based new therapeutics may meet an urgent need for new, nonopioid analgesic therapeutics to treat chronic pain.