Further Structure–Activity Relationships Study of Hybrid 7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol Analogues: Identification of a High-Affinity D3-Preferring Agonist with Potent in Vivo Activity with Long Duration of Action

Abstract

This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the phenolic hydroxyl group has been varied on the aromatic ring. Between two catechol derivatives, compound 6e with a two methylene linker length exhibited higher affinity and selectivity for D3 over D2 receptors over compound 6f with four methylene linkers (D2/D3 = 50.6 vs 7.51 for 6e and 6f, respectively). In general, the (-)-isomer was more potent than the (+)-isomeric counterpart. Binding results indicated highest selectivity for D3 receptors in compound (-)- 10 ( K i = 0.35 nM; D2/D3 = 71). In the 5-hydroxy series, highest selectivity for D3 receptors was exhibited by compound (-)- 25 ( K i = 0.82 nM; D2/D3 = 31.5). Most potent compounds exhibited binding and functional affinities at the sub-nanomolar level for the D3 receptor. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors by using tritiated spiperone as radioligand for competition studies to evaluate inhibition constants ( K i). A functional assay of selected compounds for stimulating GTPgammaS binding was carried out with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. The functional assay results indicated partial to full agonist characteristics of test compounds. Compound (-)- 25 was selected further for in vivo study to evaluate its potency in producing contralateral rotations in rats with unilateral lesion in the nigrostriatal region induced by neurotoxin 6-OHDA, a Parkinsonian animal model. Compound (-)- 25 at 5 micromol/kg exhibited rotational activity that lasted beyond 12 h, whereas at a 1 micromol/kg dose the rotations lasted beyond 8 h.

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

“…Previously, compound 15 was shown to exhibit potent agonist activity in vitro and in vivo experiments. 22 Conversion of the hydroxyl group in this compound to sulfonate ester provided 16a , 16b and 18 . Compound 16b , containing the 4-methoxy substituent, exhibited comparable activity to 4-methyl substituted 16a ( K i , D 3 = 17.6 vs 32.0 nM for 16b and 16a , respectively).…”

“…We previously characterized these molecules as potent and selective agonists for D 3 receptors. 22,25 Compounds 14a–f were designed to explore the effect of different electron withdrawing and donating groups on affinity and selectivity for the D 3 receptor. In this effort, compound 9d was converted into 14a–f by derivatization of the amino group to various sulfonamides and amides.…”

“…Next in our effort to evaluate the effect on modification of functional OH group in D 3 preferring potent agonists 15 22 and D 3 preferring compound 17 , compounds 16a–b and 18 were designed. Previously, compound 15 was shown to exhibit potent agonist activity in vitro and in vivo experiments.…”

“…Tetralone 1 was reacted with N -propylamine under reductive amination reaction conditions to give 2 , which was resolved by chiral 4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane 2-oxide, prepared according to the literature. 22 Then, N-alkylation of (±)- 2 , (+)- 2 , and (−)- 2 with ethylbromoacetate in acetonitrile in the presence of K 2 CO 3 was achieved to produce compounds (±)- 3 , (+)- 3 , and (−)- 3 in quantitative yield. Nitration of these compounds was achieved by using fuming HNO 3 to yield 7-nitro derivative (±)- 4 , (+)- 4 , (−)- 4 exclusively.…”

“…Compound 15 22 was treated with 4-methyl benzenesulfonyl chloride and 4-methoxy benzenesulfonyl chloride in the presence of triethylamine in dichloromethane to afford compounds 16a and 16b , respectively. Finally, compound 18 was achieved by reaction of known compound 17 20 with 4-methoxy benzenesulfonyl chloride.…”