1-pyrimidinyl piperazine

The metabolism of buspirone affords the inactive 5-hydroxybuspirone (OH on the 5-position of the pyrimidine ring). It is interesting that if the position is blocked, prolonged antipsychotic effects do occur. This may explain buspirone s lack of this effect. The 1-pyrimidinyl piperazine metabolite, which results from N4-dealkylation of BS, retains some activity and is being evaluated. 

Buspirone also has a weakly active metabolite, 1 -(pyrimidinyl)piperazine (1 PP), with... 

These observations question the role of noradrenaline as an initiator of anxiety as does the finding that the anti-anxiety drug, buspirone (see Chapter 9), increases the concentration of noradrenaline in the extracellular fluid in the frontal cortex of freely-moving rats (Done and Sharp 1994). Whether this is because buspirone is metabolised to l-(2-pyrimidinyl)-piperazine (1-PP), which is an a2-adrenoceptor antagonist, is uncertain. Unfortunately, no studies have investigated the effects of chronic administration of this drug on noradrenergic transmission this could be important because, unlike benzodiazepines, buspirone is effective therapeutically only after several weeks of treatment. 

The crystal structures of 4-phenyl-2- 4-[4-(2-pyrimidinyl)piperazin-l-yl]butyl -2,3,5,6,7,8-hexahydro-177-pyrido[l,2-c][l,3]oxazine-l,3-dione <1995ZK899>, 4-cyano-l-phenyl-l-trifluoromethyl-2,3-dihydro-l/7-pyrido[l,2-r-]pyrimidin-... 

B.4.2.2 Nonbenzodlazeptnes GG-NPD was used by Kivisto et al. (1999) to quantitate the nonbenzodiazepine anxiolytic buspirone and its major metabolite, l-(2-pyrimidinyl)-piperazine, using separate extraction methods and separate assays. The hmit of quantification in plasma for both compounds was 0.2 ng/mL, which makes this assay useful for pharmacokinetic studies of this compound (Kivisto et al., 1999). A rapid, simple method for analysis of buspirone in rat brain requiring a single extraction step followed by GC-NPD has also been described (Lai. et al., 1997). 

Bianchi G, Caccia S. 1988. Simultaneous determination of buspirone, gepirone, ipsapirone and their common metabolite l-(2-pyrimidinyl)piperazine in rat plasma and brain by high-performance liquid chromatography. J Chromatogr 431(2) 477-480. 

Bianchi G, Caccia S, Della Vedove F, et al The alpha-2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite l-(2-pyrimidinyl -piperazine (PMP). Eur J Pharmacol 151 365-371, 1988... 

There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)-l-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm 1. 

Zuideveld, K., Rusic-Pavletic, J., Maas, H., Peletier, L., VanDerGraaf, P., and Danhof, M., Pharmacokinetic-pharmacodynamic modeling of bus-pirone and its metabolite l-(2-pyrimidinyl)-piperazine in rats, Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 3, 2002, pp. 1130-1137. 

In 10 healthy volunteers, fluvoxamine (100 mg/day for 5 days) significantly increased the peak concentrations of the anxiolytic drug buspirone. Concentrations of the active metabolite, l-(2-pyrimidinyl)-piperazine, were reduced (23). These effects were probably mediated through inhibition of CYP3A4 by fluvoxamine. 

The interaction of itraconazole with the active l-(2-pyrimidinyl)-piperazine metabolite of buspirone has been studied after a single oral dose of buspirone 10 mg... 

The extensive oxidative metabolism of buspirone, mediated by CYP450 3A4, produces a number of hydroxy lated metabol ites including l-(2-pyrimidinyl)piperazine (1-PP), 5 -hy-dro buspirone (17) and 6-hydroxybuspirone (18) (107). After a 20-mg dose of buspirone. 

The drug is rapidly absorbed after oral administration, and peak plasma concentrations occnr abont 1 honr later. Buspirone is extensively metabolized, with less than 1% of an administered dose excreted nnchanged. Important rontes of biotransformation are hydroxylation and oxidative dealkylation, the latter yielding l-(2-pyrimidinyl) piperazines. This metabolite has been shown to concentrate in the brain and to have pharmacologic activity, thongh its capacity to interact with different brain receptors appears to differ from that of buspirone. 

Betto, P Meneguz, A. Ricciarello, G. Pichini, S. Simultaneous high-performance liquid chromatographic analysis of buspirone and its metabolite l-(2-pyrimidinyl)-piperazine in plasma using electrochemical detection. J.Chromatogr., 1992, 576, 117-121... 

Simultaneous l-(2-pyrimidinyl)piperazine, metabolites, amitriptyline, chlorpromazine, clomipramine, duphenazine, imipreimine Noninterfering caffeine, diazepam, desipramine, mianserin, zimeldine Interfering haloperidol... 

Diaz-Marot, A. Puigdellivol, E. Salvatella, C. Cornelias, L. Gassiot, M. Determination of buspirone and l-(2-pyrimidinyl)piperazine in plasma samples by high-performance liquid chromatography. 

NB Spectrophotometric value, 6.92 0.22. pKg2 reported to be 1.3 (Caccia S, Fong MH and Guiso G, Disposition of the psychotropic drugs buspirone, MJ-13805 and piribedil, and of ttieir common active metabolite l-(2-pyrimidinyl)-piperazine in ttie rat, Xenobiotica, 15 835-844, (1985)). 

D-a-Metbyldopamine (C9H13NO2) Metbylenedioxyampbetamine (MDA) (C12H19NO2) l-(3,4-Metbylenedioxybenzyl)-4-(2-pyrimidinyl) piperazine (C16H18N4O2)... 

In the buspirone analogues the l-(2-pyrimidinyl) piperazine moiety is coupled via an alkyl chain to an amide function. The bulkiness of the amide containing part of the molecules hardly influences the 5-HTlx affinity (i.e. zalospirone vs gepirone). Shortening the side chain of buspirone reduces affinity. The rankorder of potency is C-4 > C-2 > C-3 (pIC values 7.5,6.8 and 6.6 respectively) [41], Such a decrease in 5-HTu affinity is not seen in the ipsapirone series.The C-3 analogue is as potent as ipsapirone [42]. 

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