Synthesis of Dihydrofuroaporphine Derivatives: Identification of a Potent and Selective Serotonin 5-HT_1A Receptor Agonist

Abstract

A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

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

“…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.…”

“…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. Nitration of 8-hydroxy-N-methyl-1-phenylbenzazepine 10 with fuming HNO 3 and HOAc provided compounds 11 and 11 0 in 96% overall yield, with nearly no regioselectivity (1.1/1).…”

“…Acylation of amine 12 led to benzazepine 14 in 41% yield, and diethylamino-substituted benzazepine 15 was prepared in 81% yield by treating 12 with acetaldehyde and NaBH(OAc) 3 . Meanwhile, treatment [24] of 12 with 2,5-dimethoxy- Aryl methanol 18 was prepared [23] by treating phenol 9 with formaldehyde and anhydrous MgCl 2 in refluxing THF, followed by reduction with NaBH 4 in 45% overall yield (Scheme 2). Meanwhile, the benzaldehyde intermediate 17 was reacted with hydroxylamine hydrochloride followed by reduction with LiAlH 4 to afford phenylmethyl amine 19 in 58% overall yield [24].…”

“…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. N-Methylation was completed by treating amine 23 with ethyl formate followed by LiAlH 4 giving benzazepine 24 in 48% overall yield.…”

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

“…[ 35 S]GTPγS binding assays 26 were employed to determine the agonistic or antagonistic activities of compounds with K i values less than 130 nM (5b, 5c, 5d, 5i, 5k, 5o, 5m 5n), in which olanzapine was used as reference compound. The potent antagonist olanzapine of 5-HT 2A was also used as reference compound.…”