Structure-anti-Parkinson activity relationships in the aminoadamantanes. Influence of bridgehead substitution

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Abstract
A limited series of bridgehead alkyl-, dialkyl-, and trialkyl-substituted amantadines was synthesized and tested for potential anti-Parkinson activity as dopamine (DA) agonists. The compounds were evaluated using a battery of 3 murine bioassays, including stimulation of locomotor activity, induction of circling in animals with unilateral striatal lesions, and reversal of reserpine/.alpha.-methyltyrosine induced akinesia. Apparent mechanistic differences were seen between the methyl-substituted series and the ethyl-substituted series. While activities in both series increase with increasing lipophilicity, the methyl series (1b-d), as well as amantadine itself (1a), exhibits only indirect DA agonist activity, as evidenced by ipsilateral rotation in the circling model and no significant difference from control in reversal of akinesia. The ethyl series (1e,f) exhibits weak but reproducible direct DA agonist activity, as shown by contralateral rotation in the circling assay for 1e and reversal of akinesia by 1e and 1f. The 3-n-propyl derivative (1g) was devoid of any DA agonist activity.