Synthesis and binding properties of new long-chain 4-substituted piperazine derivatives as 5-HT1A and 5-HT7 receptor ligands

Modica, Maria; Intagliata, Sebastiano; Pittalà, Valeria; Salerno, Loredana; Siracusa, M. A.; Cagnotto, Alfredo; Salmona, Mario; Romeo, Giuseppe

doi:10.1016/j.bmcl.2015.02.042

Cited by 25 publications

(13 citation statements)

References 16 publications

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“…AZ-853 and AZ-861 are chemical analogs that differ only in the quality of the fluorine substituent in the phenyl ring attached to piperazine. A small change in the chemical structure may cause differences not only in chemical and physical properties but also in pharmacological and pharmacokinetic characteristics (e.g., paliperidone vs. risperidone) [ 17 – 20 ]. Our previous investigations revealed that compounds AZ-853 and AZ-861 possess high affinity for serotonergic 5-HT 1A R and are 5-HT 1A R antagonists in CHO-K1 cells in the Ca 2+ mobilization assay, with AZ-861 showing 2-fold higher K b value [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

et al. 2020

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Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT 1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT 1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H-imidazo [2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT 1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α 1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ

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Section: Discussionmentioning

confidence: 99%

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

et al. 2020

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“…[11][12][13][14] In the frame of our early stage study on serotonin receptor ligands, we developed different series of 5-HT 1A R and 5-HT 7 R ligands containing the arylpiperazine scaffold. [15][16][17] In this work, our effort was focused on the discovery of 5-HT 7 R selective ligands over 5-HT 1A R, since the level of homology of their transmembrane domains is fairly high.…”

Section: Bioorganic and Medicinal Chemistry Lettersmentioning

confidence: 99%

“…Radioligand binding assays were performed on new derivatives 13-30, 32, and 33 in order to determine the affinity and selectivity profile of the synthesized compounds for cloned human 5-HT 1A and 5-HT 7 receptors expressed in CHO-K1 cells. According to the previously reported procedure, 17 the experiments were carried out using [ 3 H]-5-HT and [ 3 H]-8-OH-DPAT as radioligands for 5-HT 7 R and 5-HT 1A R, respectively (Table 1).…”

Section: Bioorganic and Medicinal Chemistry Lettersmentioning

confidence: 99%

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

Intagliata

Modica

Pittalà

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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“…Modica et al. reported novel long‐chain 4‐substituted piperazines linked to a thienopyrimidine or quinazolines as 5‐HT 1A and 5‐HT 7 dual targeting ligands [97] . The synthesized compounds were evaluated for their binding affinity against human cloned 5‐HT 1A and 5‐HT 7 serotonin receptors.…”

Section: Recent Advancements In Piperazine Derivatives As Antidepressantsmentioning

confidence: 99%

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

et al. 2021

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Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment‐resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine‐based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine‐based therapeutic agents in early‐ or late‐phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine‐based antidepressants.

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Synthesis and binding properties of new long-chain 4-substituted piperazine derivatives as 5-HT1A and 5-HT7 receptor ligands

Cited by 25 publications

References 16 publications

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

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