trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines:  A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

Abstract

The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.

Derivatives as 5HT1A Receptor Ligands-Past and Present

“…A new class of potent and selective 5-HT 1A receptor ligands as conformationally constrained analogs of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines was reported by Perrone et al [117]. In this paper was evaluated the influence of conformational parameters of highly potent and selective 5-HT 1A receptor ligands, preparing some corresponding flexible and rigid analogues ( Table 19) [117] In particular, more conformationally constrained aryl-piperazine analogues were obtained by blocking the spacer within a cyclic structure.…”

“…In this paper was evaluated the influence of conformational parameters of highly potent and selective 5-HT 1A receptor ligands, preparing some corresponding flexible and rigid analogues ( Table 19) [117] In particular, more conformationally constrained aryl-piperazine analogues were obtained by blocking the spacer within a cyclic structure. Among the new derivatives emerged, trans 115a-e, trans 116a and trans 117a which showed a marked enhancement in 5-HT 1A receptor affinity when compared to the corresponding cis isomers.…”

Novel 4-(4-Aryl)cyclohexyl-1-(2-pyridyl)piperazines as Δ8−Δ7 Sterol Isomerase (Emopamil Binding Protein) Selective Ligands with Antiproliferative Activity

“…We had followed a similar approach to prepare some arylpiperazine derivatives as serotonin 5-HT 1A receptor ligands. 23 Therefore, we screened a restricted series of these N-arylpiperazines and related compounds, choosing among the lowest-affinity ligands for serotonin 5-HT 1A , dopamine D 2 , and adrenergic R 1 receptors, and testing them for EBP, σ 1 and σ 2 affinity (Chart 4). The results allowed to highlight the high-affinity and selective EBP ligand cis-4-[4-(2-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (cis-19) as a lead compound (Table 1).…”

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

“…Although the angular geometries of arylpiperazines at the receptor binding site cannot be excluded, at present extended conformations are generally accepted as bioactive [28,29] (e.g. represented by constrained compounds 23 and 24).…”