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.
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.
Claudi
F
F
Cristalli
G
G
Martelli
S
S
Perlini
V
V
Massi
M
M
Venturi
F
F
D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011388:Prolactin / Q000097:blood; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship
D004873:Ergolines; D010618:Phenanthrolines; D011758:Pyrroles; D011954:Receptors, Dopamine; D001971:Bromocriptine; D011388:Prolactin