New potent 5-HT2A receptor ligands containing an N′-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation

Synthesis, docking studies, and pharmacological evaluation of 5HT2C ligands containing the N′‐cyanoisonicotinamidine or N′‐cyanopicolinamidine nucleus

“…In conclusion, data presented in this study demonstrate that, surprisingly, the novel synthesized compounds did not display a general trend of affinity towards 5‐HT 1A or 5‐HT 2A receptors, as instead obtained with the series previously synthesized . On the other hand, the here reported compounds are characterized by an important 5‐HT 2C affinity/activity profile and molecular docking studies supported these results highlighting some selective and additional interactions of the identified ligands with the 5HT 2C receptor subtype.…”

“…The two series, 4a–e and 8a–e , differ in the presence of a N ′‐cyanoisonicotinamidine or N ′‐cyanopicolinamidine nucleus connected through an alkyl chain (three units) to 4‐substituted piperazines. Some derivatives ( 4a , 4b , 8a , and 8b ) have been already reported in two studies concerning N ′‐cyanoisonicotinamidine and N ′‐cyanopicolinamidine derivatives, whereas general trend a N ′‐cyanoisonicotinamidine scaffold represents an optimal structural element to enhance 5‐HT 1A receptor binding, whereas the N ′‐cyanopicolinamidine nucleus drives the binding more toward 5‐HT 2A receptor. The cyanoamidine group as well as the different position of nitrogen into the aromatic system of the considered nuclei do not seem to be decisive in determining a specific profile towards 5‐HT 2C receptors subtype but the affinity/selectivity profile was more influenced by the particular substituent on the piperazine moiety.…”

“…In particular, much effort has been devoted to understand both the role of the heterocyclic nucleus and of the substituent on the piperazine scaffold in the ligand–receptor interaction and, consequently, a great number of different fragments were used . In our laboratories, there has been an ongoing research work to develop more selective serotoninergic ligands to have novel pharmacological tools that could improve our knowledge of the signal transduction mechanism leading to compounds with high affinity and selectivity. Previously described studies focused on the synthesis and pharmacological evaluation of a set of arylpiperazine derivatives containing a N ′‐cyanoisonicotinamidine or N ′‐cyanopicolinamidine nucleus; the binding data reported in these studies identified this original scaffold as an optimal structural element to enhance 5‐HT 1A and 5‐HT 2A receptor affinity respectively .…”

“…In our laboratories, there has been an ongoing research work to develop more selective serotoninergic ligands to have novel pharmacological tools that could improve our knowledge of the signal transduction mechanism leading to compounds with high affinity and selectivity. Previously described studies focused on the synthesis and pharmacological evaluation of a set of arylpiperazine derivatives containing a N ′‐cyanoisonicotinamidine or N ′‐cyanopicolinamidine nucleus; the binding data reported in these studies identified this original scaffold as an optimal structural element to enhance 5‐HT 1A and 5‐HT 2A receptor affinity respectively . Successively, we designed a new set of derivatives where the piperazine‐ N ‐alkyl moiety has been linked to an isonicotinic or picolinic fragment as terminal part of LCAPs; this choice was made considering that it represents a molecular simplification of previously synthesized derivatives .…”

Synthesis and In Vitro Pharmacological Evaluation of Novel 2‐Hydroxypropyl‐4‐arylpiperazine Derivatives as Serotoninergic Ligands

“…The dopaminergic D 2 receptor and α 1 ‐adrenoceptor are two examples of receptors for which several 5‐HT 1A ligands show high affinity. In our laboratories, there has been an ongoing effort to develop more selective serotoninergic ligands in order to have novel pharmacological tools that could improve our knowledge of the signal transduction mechanism leading to compounds with high affinity and selectivity . In continuation of our research program, we designed a new set of derivatives where the piperazine‐N‐alkyl moiety has been linked via a 2‐hydroxy‐propyl spacing unit to a norbornene and an exo‐ N ‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboximide nucleus, respectively.…”