New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT_1A/5‐HT₇ Receptor Ligands

Abstract

A series of new long-chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5-HT(1A) and 5-HT(7) receptor ligands. The compounds were prepared by a two-step procedure using naphthalimide and 2H-1,3-benzoxazine-2,4(3H)-dione as imides, and 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1,2,3,4-tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta- and hexamethylene chains as well as partly constrained m- and p-xylyl moieties. In general, the new compounds were more active at the 5-HT(1A) than at the 5-HT(7) receptor, and the o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o-OMe-PhP series, except for a small binding reduction for ligands containing the m-xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure-activity relationship was visible only for the interaction of the compounds with the 5-HT(7) receptor, which strongly favored flexible analogs.

The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors

“…The synthesis of p ‐benzylmethylamines 24 and 25 was carried out using N ‐[4‐(chlorometyl)benzyl]phthalimide ( 21 ) as the starting compound (Scheme ). The intermediate 21 was obtained by reacting phthalimide with α,α′‐dichloro‐ p ‐xylene as described previously . The reaction of 21 with o ‐OMe‐PhP or 2,3‐DCPP, carried out in DMF in the presence of K 2 CO 3 at ambient temperature, afforded N ‐alkylated phthalimides 22 and 23 , respectively.…”

“…In the terminal part of the molecules studied phenyl, 2‐naphthyl, or methyl group was introduced. In comparison with the classic LCAP we replaced an alkylene spacer with partly constrained p ‐xylyl ( 9 – 11 , 15 – 17 ) and benzyl ( 12 – 14 , 18 – 20 ) fragment, because the effect of the spacer structure in LCAP ligands was the subject of our subsequent research .…”

N‐{[2‐(4‐Phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides with Dopamine D2 and 5‐Hydroxytryptamine 5HT1A Activity: Synthesis, Testing, and Molecular Modeling

“…Arylpiperazines as dopaminergic and serotonergic compounds can indorse the whole range of functional activities; they can be antagonists, partial agonists, or full agonists . Here we concentrate solely on to the binding properties of the reported compounds.…”

“…N‐ Arylpiperazines are example of the so‐called “privileged structures” that are present in numerous high‐affinity ligands for different G‐protein coupled receptors . They can be agonists, partial agonists, or full agonists in D 2 , 5‐HT 1A , 5‐HT 2A , 5‐HT 7 , α1‐, and β1‐adrenergic receptor systems . It is rather difficult to predict binding and functional properties of N ‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides on different receptor systems solely on the basis of literature data.…”

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

“…A very important class of 5-HT receptors ligands are derivatives of 1,4-disubstituted arylpiperazine ( Figure 1). Such arylpiperazine derivative with longchain substituents incorporated on the basic nitrogen of the phenylpiperazine ring -long-chain arylpiperazines (LCAPs) -are commonly studied classes of bioactive compounds [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Despite the enormous progress in central nervous system (CNS) drug discovery, particularly in the areas of mood disorders and schizophrenia, new drugs are still being sought.…”