Synthesis and preliminary biological evaluation of new alpha-amino amide anticonvulsants incorporating a dextromethorphan moiety.

Dextromethorphan 1 is an effective neuroprotectant in animal models of epilepsy and ischemia but showed side-effects during clinical trials limiting its potential use in a clinical setting. Here we describe the enantioselective and enantiospecific syntheses and the initial in vitro and in vivo biological evaluation of new hybrid structures between 1 and a previously disclosed alpha-amino amide anticonvulsant (3).

Synthesis and in vitro and in vivo evaluation of dopaminergic ergoline derivatives.

A series of ergoline-amides was synthesised in the discovery of new dopaminomimetic agents. Several compounds exhibited in vivo high prolactin lowering activity (indirectly measured by the nidation test) in rats. For the most active, the potential anti-Parkinson activity was evaluated by observation of the contralateral turning behaviour in 6-OH-DA lesioned rats. The acute toxicity by oral route in mice was also studied.

Antihypertensive ergoline derivatives.

Novel ergolines were synthesized and screened in spontaneous hypertensive rats (SHR) with the aim of finding a new class of ergot related antihypertensives. Their prolactin inhibitory effect (measured as nidation inhibition in rats), acute toxicity (LD50) and interference with CNS function (Irwin test) were also evaluated as a measure of selectivity and safety. Modification of the C8 side-chain enhanced antihypertensive activity selectively, while the introduction of substituents in other positions of the ergoline skeleton generally yielded unfavourable results, either by decreasing selectivity or by increasing toxicity.