title: Synthesis and central dopaminergic activities of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-9-oxaergolines].
abstract: The synthesis and biological activities of a series of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-trans-9-oxaergolines] with central dopamine (DA) agonist properties are described. The compounds were prepared from [2aRS-(2a alpha,4 beta,5 alpha)]-4-amino-1,2,2a,3,4, 5-hexahydro-1-(phenylmethyl)benz[cd]indol-5-ol (6b) by alkaline cyclization of the corresponding N-chloracetamide 7b, followed by reduction of the amido group [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,7,9, 10a-octahydro-4-(phenylmethyl)-7H-indolo[3,4-gh][1,4]benzoxazin-8-one (8b) with LiAlH4. After debenzylation of the resulting amine 9a, the indoline ring of [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,8,9, 10a-octahydro-7H-indolo[3,4-gh][1,4 ]benzoxazine (10a) was dehydrogenated with MnO2 to give (+/-)-trans-9-oxaergoline (11a), which can be alkylated on the nitrogen (11b,c and 12) and brominated in position 2 (13a,b). The compounds were examined in vitro for their ability to bind to DA receptors and to inhibit prolactin (PRL) secretion in pituitary cells in culture, in vivo both for their DA stimulant effects at the striatal level (circling in 6-OHDA-lesioned animals, DA turnover, and stereotypy) and inhibitory effects on plasma PRL levels in rats, and for their emetic effects in dogs. Most of the tested compounds were active in these tests, and the potency of (+/-)-trans-6-n-propyl-9-oxaergoline (11c) was comparable to that of pergolide mesylate.
mesh_terms: D000818:Animals; D004285:Dogs; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced
chemical_list: D004873:Ergolines; D010078:Oxazines; D011954:Receptors, Dopamine; D011388:Prolactin