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Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols with promising anticonvulsant and analgesic activity.

Bioorg Med Chem Lett. 2019 Apr 4. pii: S0960-894X(19)30215-X. doi: 10.1016/j.bmcl.2019.04.006. [Epub ahead of print]

Authors/Editors: Gunia-Krzyżak A, Bareyre FM, Marona H, Waszkielewicz AM.
Publication Date: 2019



Epilepsy and neuropathic pain are frequent neurological disorders with pathomechanism based on abnormal neuronal discharges. Secondary tissue impairment observed after traumatic brain injury is also connected with neuronal dysfunction. Those three neurological disorders are ineffectively treated with currently available pharmacotherapy options so great effort is made in searching for new effective drugs. Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide, R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide, R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide, (2E)-3-(4-chlorophenyl)-N-(4-hydroxycyclohexyl)prop-2-enamide were evaluated in vivo and in vitro for anticonvulsant, neuroprotective and/or analgesic activity. In intravenous metrazol seizure threshold test compounds 1–3 did not show pro-convulsive effect but proved anticonvulsant potential. In corneal kindled mice model the tested compounds showed beneficial anticonvulsant properties with ED50 of 36.8 mg/kg for 1, 25.7 mg/kg for 2, and 51.1 mg/kg for 3. Compound 2 tested in vitro in spontaneously bursting rat hippocampal slice model significantly reduced burst rate. Compounds 1 and 2 did not decrease lesion volume in acute model of traumatic brain injury. In formalin test of hyperalgesia in mice, compound 1 was active in the acute phase of the test, while compound 4 caused reduction of the time of licking of the affected paw by approx. 88% during the acute phase and 100% during the inflammatory phase. In rat sciatic ligation model of neuropathic pain, compound 1 significantly increased the paw withdrawal threshold starting from one hour after oral administration and the activity continued up to six hours. Reported here four N-(E)-cinnamoyl derivatives of aminoalkanols possess promising activity as anticonvulsant and/or analgesic agents.

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