Preparation and pharmacological characterization of trans-2-amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes as D2-like dopamine receptor agonists.
The present work reports the synthesis of trans-2-amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (4a-f, 5a-f) as a continuation of our studies to better understand the significance of the halo substituent in the trans-1-phenyl-2-aminoindane series and to extend knowledge of the monophenolic ligands of DA receptors. The affinity of the new compounds and related methoxylated precursors (10-15 and 18-23) was estimated in vitro by displacement of [(3)H]SCH23390 (for D(1)-like receptors) or [(3)H]YM-09-151-2 (for D(2)-like receptors) from homogenates of porcine striatal membranes. The results indicate that unsubstituted amines 4a, 5a, 10, and 11 are poorly effective at DA receptors. The introduction of two n-propyl groups on the nitrogen atom (compounds 14, 15, 4c, and 5c) and N-allyl-N-methyl- or N-methyl-N-propyl- substitution (compounds 20-23, 4e, 4f, 5e, 5f) increased the D(2)-like affinities and selectivity. The D(2)-like agonistic activity of selected compounds 15, 20, 21, 4e, 5c, and 5e was proved by evaluating their effects on the cyclic guanosine monophosphate (cGMP) content in rat neostriatal membranes. All tested compounds displayed a potential dopamine D(2)-like agonist profile decreasing basal levels of cGMP. The selective D(2)-like agonism of compounds 20 and 5e was proved by their effects on basal striatal adenylyl cyclase activity.
Di Stefano
Antonio
A
Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Sozio
Piera
P
Cacciatore
Ivana
I
Cocco
Alessandra
A
Giorgioni
Gianfabio
G
Costa
Barbara
B
Montali
Marina
M
Lucacchini
Antonio
A
Martini
Claudia
C
Spoto
Giuseppe
G
Di Pietrantonio
Francesco
F
Di Matteo
Elisabetta
E
Pinnen
Francesco
F
D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D065127:Dopamine D2 Receptor Antagonists; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013552:Swine
D065127:Dopamine D2 Receptor Antagonists; D007192:Indenes; C500166:N-methyl-N-n-propyl-2-amino-5-fluoro-6-hydroxy-1-phenyl-2,3-dihydro-1H-indene; C500165:N-methyl-N-n-propyl-2-amino-6-fluoro-5-methoxy-1-phenyl-2,3-dihydro-1H-indene; D017448:Receptors, Dopamine D2; D000242:Cyclic AMP; D006152:Cyclic GMP