Arylpiperazine derivatives of 3-propyl-beta-tetralonohydantoin as new 5-HT1A and 5-HT2A receptor ligands.

A series of new analogues of 3-[3-(4-arylpiperazinyl)-propyl]-cyclo-hexane-1',5-spirohydantoin (2), with aromatic ring fused in amide moiety (4-9) were synthesized and evaluated for affinity at 5-HTIA and 5-HT2A receptors. The influence of the substitution mode in the phenyl ring of phenylpiperazine moiety on the affinity for both receptors has been discussed. The most potent 5-HTIA (9, Ki = 53 nM) and 5-HT2A (4, 6, 8 and 9; Ki = 14-76 nM) ligands were evaluated in in vivo tests. The obtained results indicate that all in vivo tested compounds showed pharmacological profile of 5-HT2A antagonists. Additionally, a m-CF3 derivative (9), behaved like a partial agonist (agonist of pre- and antagonist of postsynaptic) of 5-HTIA receptors and may offer a new lead for the development of potential psychotropic agents.

[1]  L. Pardo,et al.  Synthesis and structure-activity relationships of a new model of arylpiperazines. Study of the 5-HT(1a)/alpha(1)-adrenergic receptor affinity by classical hansch analysis, artificial neural networks, and computational simulation of ligand recognition. , 2001, Journal of medicinal chemistry.

[2]  P. Grieco,et al.  Synthesis of new 1,2,3-benzotriazin-4-one-arylpiperazine derivatives as 5-HT1A serotonin receptor ligands. , 2000, Bioorganic & medicinal chemistry.

[3]  M. López-Rodríguez,et al.  Synthesis and structure-activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure-activity relationships of hydantoin-phenylpiperazine derivatives with affinity for 5-HT1A and alpha 1 receptors. A comparison of CoMFA models. , 1997, Journal of medicinal chemistry.

[4]  B. Łozowicka,et al.  The structure of 3[4-(4-phenylpiperazine)butyl]-5,5-diisopropylhydantion-new ligant of serotonin receptors. , 1997 .

[5]  M. Pawłowski,et al.  3‐(ω‐Aminoalkyl)‐5,5‐dialkyl(or spirocycloalkyl‐1′,5‐)hydantoins as New 5‐HT1A and 5‐HT2A Receptor Ligands. , 1996 .

[6]  I A Cliffe,et al.  A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. , 1995, European journal of pharmacology.

[7]  H. Berendsen,et al.  Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats. , 1991, Behavioral and neural biology.

[8]  R. Glennon,et al.  Do functional relationships exist between 5-HT1A and 5-HT2 receptors? , 1990, Pharmacology Biochemistry and Behavior.

[9]  H. Berendsen,et al.  Selective activation of 5HT1A receptors induces lower lip retraction in the rat , 1989, Pharmacology Biochemistry and Behavior.

[10]  C. B. Davis,et al.  Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy. , 1989, Journal of medicinal chemistry.

[11]  G. Goodwin,et al.  The pharmacology of the hypothermic response in mice to 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT) A model of presynaptic 5-HT1 function , 1985, Neuropharmacology.

[12]  J. Springer,et al.  Bioactive conformation of 1-arylpiperazines at central serotonin receptors. , 1985, Journal of medicinal chemistry.

[13]  R. Fuller,et al.  Structural relationships in the inhibition of [(3)H]serotonin binding to rat brain membranes in vitro by 1-phenyl-piperazines. , 1980, Biochemical Pharmacology.

[14]  J. I. DeGraw,et al.  Substituted 1,2,3,4-tetrahydro- -carbolines , 1967 .

[15]  W. H. Burton,et al.  Potential Growth Antagonists. I. Hydantoins and Disubstituted Glycines1,2 , 1960 .