N-Propylnoraporphin-11-O-yl carboxylic esters as potent dopamine D2 and serotonin 5-HT1A receptor dual ligands

Identification of N-Propylnoraporphin-11-yl 5-(1,2-Dithiolan-3-yl)pentanoate as a New Anti-Parkinson's Agent Possessing a Dopamine D2 and Serotonin 5-HT1A Dual-Agonist Profile

“…(6α R )-(−)-11-Hydroxy- N -propylnoraporphine (−)- 6 and its racemate, (±)- 6 , were used as the key intermediates. The optically pure aporphine (−)- 6 ,, was prepared from natural alkaloid morphine in six steps as described previously by us. The racemate (±)- 6 was prepared by total synthesis from Reissert salt and arylmethyl bromide in eight steps according to a literature procedure.…”

“…The tetracyclic skeleton of aporphine analogues (aporlogues), represented by the prototypic compound ( R )-(−)-apomorphine [(−)- 4 (Figure )], is a long-standing scaffold for the D 2 receptor agonists. − We and others − have reported that introducing a more lipophilic group at C10, C11, or both led to compounds like (−)- 5 with a complete loss of affinity for the D 2 receptor, but with high potency and selectivity toward the 5-HT 1A receptors, indicating a 5-HT 1A binding site existing in the D 2 agonist scaffold. Further, D 2 and 5-HT 1A dual-receptor activity was observed in the ester derivatives [e.g., (−)- 7 ] of ( R )-(−)-11-hydroxy- N -propylnoraporphine [(−)- 6 ]. In our preliminary study, compound (−)- 7 had a significant antiparkinsonian effect; however, it suffered from a short half-life and exerted an only moderate effect on LID in rats (data not shown).…”

‘Click’ D1 receptor agonists with a 5-HT1A receptor pharmacophore producing D2 receptor activity

“…This procedure is similar to those reported by us previously. 15,19,20 (2) were also tested in our assays for comparison. Compound 8a which contains an ortho-tolyl as the C1 substituent in the benzazepine core and pyrimidin-2-yl (Pym) as the aryl group did not show binding affinity at both D 1 and D 2 receptors; however, some affinity (K i , 800 nM) was observed at the 5-HT 1A receptor.…”

“…Membrane homogenates of 5-HT 1A -CHO cells, D 1 -or D 2 -HEK293 cells were prepared as described previously. 15 5-HT 1A , SCH23390 for D 1 , or spiperone for D 2 dopamine receptors, respectively. The reaction was started by addition of membranes (15 lg/tube) and stopped by rapid filtration through Whatman GF/B glass fiber filter and subsequent washing with cold buffer (50 mM Tris, 5 mM EDTA, pH 7.4) using a Brandel 24-well cell harvester.…”

“…Therefore, it has been proposed that 5-HT 1A agonists combined with DA receptor agonism or antagonism may be an optimal option for treating these disorders. [14][15][16][17] In fact, sarizotan, a compound possessing high binding at both D 2 and 5-HT 1A receptors, and acting as a 5-HT 1A agonist and D 2 receptor partial agonist/ antagonist, has been found in effectively improving DA-induced motor complications by reducing striatal serotoninergic nerve impulse activity without altering L-dopa efficacy. These compounds have been in clinical trial as an innovative bisfunctional drug for treating dyskinesias associated with L-dopa therapy in PD.…”