RESUMO
Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT(3)) receptor. Most of the new compounds show subnanomolar 5-HT(3) receptor affinity. Ester 6bc showing a picomolar K(i) value is one of the most potent 5-HT(3) receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT(3) receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT(3) receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT(3) receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
Assuntos
Acetilcolinesterase/metabolismo , Acridinas/síntese química , Inibidores da Colinesterase/síntese química , Piperazinas/síntese química , Quinolinas/síntese química , Receptores 5-HT3 de Serotonina/metabolismo , Acetilcolinesterase/química , Acridinas/química , Acridinas/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Córtex Cerebral/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Simulação por Computador , Humanos , Técnicas In Vitro , Ligantes , Masculino , Modelos Moleculares , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
Assuntos
Pirrolidinonas/química , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Área Sob a Curva , Humanos , Absorção Intestinal , Ligantes , Masculino , Taxa de Depuração Metabólica , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Ensaio Radioligante , Receptores 5-HT3 de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.