A New Arylpiperazine Antipsychotic with High D2/D3/5-HT1A/.alpha.1A-Adrenergic Affinity and a Low Potential for Extrapyramidal Effects

Distribution and metabolism of the antipsychotic agent mazapertine succinate in rats

“…Comparison of the EI data Fig. 3, these shifts in m/z suggested that the oxidation in M3 had occurred on both Rings A and D. 1 H NMR data revealed that M3 contained one less aromatic proton on Ring A consistent with the MS data. The aromatic proton pattern of the three remaining protons on Ring A suggested that the para-position relative to the piperazine ring had been hydroxylated.…”

“…Mazapertine (1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoy]piperidine succinate, RWJ-37796, Mz) has been shown to be an effective antipsychotic agent which binds with high affinity to D 2 , D 3 , 5-HT 1A and ␣ 1A -adrenergic receptors [1][2][3]. Preliminary results on the psychopharmacological profile and pharmacokinetics of Mz in healthy male volunteers have been reported [4,5].…”

“…The excretion of Mz and these metabolites in plasma, urine and feces are discussed along with the key pharmacokinetic parameters. 14 C Mz, Mz [1], metabolite M1 (RWJ-50503) [9], metabolite M2 (RWJ-48772) [9], metabolite M4 (RWJ-50292) [9], metabolite M7 (RWJ-47999) [9], M11 (RWJ-48278) [9] and metabolite M14 (RWJ-380037) [9] …”

Interactions between neuroleptics and 5-HT 1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects

“…Interest in the possible role of 5-HT 1A receptors in EPS has been stimulated further by the recent finding that the atypical neuroleptic clozapine, which lacks almost completely the ability to induce EPS, has partial 5-HT 1A agonist properties (Seeger et al 1995;NewmanTancredi et al 1996;Assié et al 1997). The growing interest in 5-HT 1A receptors in neuroleptic research is evidenced by reports of novel antidopaminergic compounds with affinity for 5-HT 1A receptors (e.g., Barnes et al 1991;Hrib et al 1991;Reitz et al 1994;Seeger et al 1995;Norman et al 1996;Perrone et al 1997). A number of such mixed compounds are in clinical development, or have already been marketed (e.g., ziprasidone, nemonapride and mazapertine).…”

“…For example, neuroleptic-induced catalepsy is attenuated not only by the prototypical 5-HT 1A agonist 8-OH-DPAT, but also by partial agonists such as ipsapirone or BMY 14802 (McMillen et al 1988). Studies of the role of intrinsic activity appear to be especially relevant because novel antidopaminergic compounds with substantial affinity for 5-HT 1A receptors vary widely with respect to their intrinsic activity at these receptors, which is high for some (e.g., ziprasidone and nemonapride), and intermediate (e.g., clozapine) or low (e.g., perospirone, bromerguride) for others (Kato et al 1990;Reitz et al 1994;Seeger et al 1995;Newman-Tancredi et al 1996;Assié et al 1997). Currently, systematic data on the relationship between the intrinsic activity of 5-HT 1A ligands and their effects on the EPS liability and the antipsychotic potential of antidopaminergic compounds are lacking.…”