Synthesis and dopaminergic activity of trans-6-methyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]-4,7-phenanthroline and trans-1,2,3,4,4a,5,6,10b-octahydro-4,7-phenanthroline derivatives

Abstract

The synthesis and dopamine agonist activity of some derivatives of trans-6-methyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6a-c) are reported. These compounds can be regarded as analogues of ergoline derivatives with the indole nucleus replaced by indolizine. These congeners have been evaluated as inhibitors of prolactin release in vivo. trans-6-Methyl-8-ethyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6b) proved to produce a dose-dependent inhibition of serum prolactin that was almost complete at the highest dose employed. Although effective, this compound was far less potent than bromocriptine. The 8-propyl derivative 6c was weakly active only at very high doses, and the 8-methyl derivative 6a proved to be completely ineffective. trans-4-Propyl-1,2,3,4,4a,5,6,10b-octahydro-4,7-phenanthroline (7), a molecular simplification of hexahydropyrrolo-4,7-phenanthroline, proved to be the most potent among the newly synthesized compounds. These results, taken together with those of previous studies, suggest that the presence of the nitrogen of the indolizine nucleus and the N-7 in the octahydro-4,7-phenanthroline 7 are significant for the interaction with the dopamine receptor involved in the control of prolactin release.

Heterocycles with a bridgehead nitrogen atom. 16. Assembly of a peri-fused system from an angular tricycle by recyclization of an oxazole ring into pyrrole one

“…Compounds of this class first obtained in the 1980s 7,8 attracted attention as agonists of dopamine receptors. 9 Note that amino or alkoxy derivatives of this system have been unknown hitherto. Our subsequent studies will be devoted to the effects of the substituent nature in the pyridine ring and the size of the saturated fragment in system 6 on the recyclization in question.…”