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-HT_1A Dual-Agonist Profile

Abstract

A series of new aporphine analogues (aporlogues) were synthesized bearing a C-, N-, or O-linkage at the C11 position. Lipoic ester (-)-15 was identified as a full agonist at the dopamine D(2) and serotonin 5-HT(1A) receptors with K(i) values of 174 and 66 nM, respectively. It elicited antiparkinsonian action on Parkinsin's disease (PD) rats with minor dyskinesia. Chronic use of (-)-15 reduced L-DOPA-induced dyskinesia (LID) without attenuating the antiparkinsonian effect. These results suggest that 5-HT(1A) and D(2) dual-receptor agonist (-)-15 may present a novel candidate drug in the treatment of PD and LID.

Structural manipulation on the catecholic fragment of dopamine D1 receptor agonist 1-phenyl-N-methyl-benzazepines

“…Meanwhile, to evaluate the selectivity of these compounds among the DA receptor subtypes, binding affinities at the D 2 and D 3 receptors were also tested. The procedure is similar to those reported by us previously [12,13,22,23]. As shown in Table 1, significant discrepancy in D 1 receptor binding was observed between the two mono-hydroxyl benzazepines 9 and 10.…”

“…Therefore, to quickly identify new compounds for further study, all compounds in current report were prepared and evaluated as racemates. As shown in Scheme 1, by following a literature procedure [12,13,22,23], 7-and 8-methoxy-N-methyl-1-benzazepines 7 and 8 were prepared from corresponding 3-or 4-methoxyphenyl ethanamine and 2-phenyloxirane in three steps [18,19]. Removal [23] of the Omethyl group by refluxing in 48% HBr aqueous solution led to monohydroxyl benzazepines 9 and 10 in 90% yield.…”

“…Synthesis of 7-aryl substituted benzazepine analogues 21aee was described in Scheme 3. Bromination of 8-methoxy-3-H-benzazepine 8 0 followed by N-methylation provided bromide 20 in 40% yield, which was then subjected to palladium-catalyzed Suzuki coupling with arylboronic acids followed by O-demethylation [22] with BBr 3 at À78 C to deliver target compounds 21aee in 27e73% overall yields. Meanwhile, triflation of 7-and 8-hydroxylbenzazepines 9 and 10 with Tf 2 O and Et 3 N, followed by Pd(OAc) 2 -catalyzed CeN bond formation [23] and subsequent hydrolysis provided 7-and 8-aminobenzazepines 22 and 23 in 82% overall yields.…”

“…To investigate the selectivity of our newly synthesized benzazepine analogues over the 5-HT receptors, binding assays of the D 1 -active compounds were further evaluated at the 5-HT 1A and 5-HT 2A receptors by using [ 3 H]8-OH-DPAT and [ 3 H]ketanserin as the respective standard radioligands [12,13,22,23]. As summarized in Table 3, most of these compounds displayed moderate to high affinities at the 5-HT 2A receptor, yet low or no affinities at the 5-HT 1A receptor.…”

Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold

“…HCl to get the corresponding hydrochloride salt. The receptor binding assays were conducted according to our previous published protocol 22,23 . For the initial screening, the inhibition percentages of the compounds 5a-5v at 10 μM were measured and the values of K i were given only when the inhibition rate of compound was greater than 90%.…”