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

Abstract

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.

Dopamine D2 receptor-dependent modulation of striatal NO synthase activity

“…For instance, we found that electrical and chemical stimulation of the substantia nigra (SN) and systemic DA D 1 receptor agonist administration both robustly increase striatal NO efflux via nNOS and DA D 1 receptor-dependent mechanisms (Sammut et al 2006). In agreement with our study, DA D 1 receptor activation has been shown to increase striatal tissue levels of the NO second messenger cGMP (Altar et al 1990;Di Stefano et al 2005;Siuciak et al 2006b). Conversely, DA D 2 receptor activation decreases striatal tissue levels of cGMP (Di Stefano et al 2005).…”

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

“…Remarkably consistent outcomes have been reported in studies examining the impact of DA D1 and D2-like receptor agonists/ antagonists on striatal NOS activity and NO production via cGMP (Di Stefano et al, 2005;Sammut et al, 2006;Siuciak et al, 2006;Park and West, 2009;Hoque et al, 2010).…”

Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

“…Striatal elevation of cGMP is another common feature of D2 antagonists (Altar et al, 1990;Di Stefano et al, 2005), PDE10A inhibitors , and PDE9A inhibitors. However, in contrast to antipsychotics and PDE10A inhibitors, the PDE9A inhibitors did not affect spontaneous or stimulant-induced locomotor activity or conditioned avoidance responding.…”