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

Abstract

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.

Figure 1

Scheme 1

Reagents and conditions: (a) n-Propylamine, NaCNBH₃, AcOH, 1,2-dichloroethane; (b) (+) or (−) chlocyphos, ethanol, recrystallized from isopropanol; (c) BrCH₂ CO₂ Et, K₂ CO₃, AcCN; (d) fuming HNO₃; (e) (i) 10% Pd/C, H₂, EtOH, (ii) AcCI, Et₃N, CH₂ CI₂; (f) fuming HNO₃; (g) (i) conc, HCI, (ii) EDCI, HtOH, 1-(2-substituted phenyl)piperazine, CH₂CI₂; (h) (i) 10% Pd/C, H₂, CH₃ OH, (ii) BH₃, THF; (i) HCOOH; (j) CS₂, KOH, EtOH; (k) 1,1′-carbonyldiimidazole, AcCN; (I)CNBr, H₂O.

Scheme 2

Reagent and conditions: (a) Bromoacetaldehyde diethyl acetal, Na₂CO₃, EtOH, reflux; (b) (CF₃CO)₂/CF₃ COOH, reflux; (c) MeOH, reflux; (d) YXCI, pyridine (for 14a, 4-CIC₆H₄SO₂CI; for 14b, 4-CF₃C₆H₄SO₂Cl); for 14c, PhCOCI; for 14d, AcCI; for 14e, 4-CH₃C₆h₄SO₂Cl; for (±)14f and (+)14f, 4-CH₃OC₆h₄SO₂Cl).

Scheme 3

Reagents and conditions: (a) YXCI, Et₃N, DCM, over night (For 16a, 4-CH₃C₆H₄SO₂Cl; for 16b and 18, 4-CH₃OC₆H₄SO₂Cl).