Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents

Abstract

The binding of a series of phenylpiperazines (3) and benzoylpiperazines (4) to central serotonin (5-HT) sites was investigated. Several derivatives of 3 displayed nanomolar affinities for 5-HT1 sites, whereas derivatives of 4 were essentially inactive both at 5-HT1 and 5-HT2 sites. 1-(2-Methoxyphenyl)piperazine (2-MPP, 3a) was found to possess an affinity (Ki = 35 nM) for 5-HT1 sites comparable to that of the recognized 5-HT agonist 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (Ki = 20 nM); 3a also displayed a 100-fold selectivity for 5-HT1 sites (as compared to 8-fold for TFMPP). In tests of stimulus generalization using rats trained to discriminate TFMPP (ED50 = 0.17 mg/kg) from saline, 3a was found to be nearly equipotent (ED50 = 0.22 mg/kg) with the training drug. These results suggest that 3a may be a novel and more selective 5-HT1 agonist than TFMPP.

Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol

“…The resultant pellet was homogenized in buffer A and centrifuged again. The final pellet was resuspended in buffer A containing 120 mM NaC1, 5 Tubes were incubated a t 37 "C for 20 min and rapidly filtered under vacuum through Whatman GF/B filters with four rinses of ice-cold 50 mM buffer A. The filters were placed in scintillation vials containing 10 mL of Scintisol and left overnight.…”

Metabolism of Designer Drugs of Abuse

“…Only very little is known on the pharmacology and toxicology of MeOPP. Its two-methoxy isomer is known to show serotonergic and dopamine antagonistic properties and its effects have been described as similar to those of TFMPP [99,104,110,170,171]. Therefore, in analogy to other 1-arylpiperazines, especially to the above-mentioned compounds, similar effects might be assumed for MeOPP.…”

Toxicological detection of the new designer drug 1-(4-methoxyphenyl)piperazine and its metabolites in urine and differentiation from an intake of structurally related medicaments using gas chromatography–mass spectrometry

“…So far, only little information is available about the pharmacological and toxicological properties of MeOPP. However, as other 1-arylpiperazines are known to show central serotonergic effects [17][18][19][20][21], it can be assumed that MeOPP shows similar effects.…”