The objective of this proposal is the continued synthesis and development of anti-convulsant drugs related to 1) those dopamine agonists which can be considered as congeners of apomorphine, 9,8-dihydro-6H-dibenzo[c,g]azonines, and amonotetralin, and 2) aminoisoquinolines, and their evaluation as anticonvulsant drugs in the Anticonvulsant Screening Project (ASP) carried out by the NINCDS. In this research program we shall also investigate 1) the relationship of dopamine agonist response on the basis of the activity on DA sensitive adenylate cyclase, the competition of binding to various 3H-ligands compared with their anticonvulsant activity both from the ASP screen and from audio- or photic-induced seizures in rodents and baboons; 2) the continued study of the chemistry of aminoisoquinoline to make structural changes in this heterocyclic system and to assess the SAR in a systematic approach to structural modification; 3) the study of the acid catalyzed rearrangement of opium alkaloids which would lead to novel aporphines and related structures of interest for biological evaluation; 4) the continued development of sensitive methods for the quantification of N-n-prophylnorapomorphine (NPA), 2,10,11-trihydroxyaporphine (TNPA) and certain pro-drug derivatives of these agents in biological fluids using electron capture gas chromatography in combination with mass spectrometry. In order to facilitate absorption and pharmacokinetic properties, pro-drug derivatives of the most active anticonvulsant compounds will be investigated.
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