Pyrimidinylpiperazine Explained

1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine derivative. It is known to act as an antagonist of the α₂-adrenergic receptor (K_i = 7.3–40 nM)^[1] and, to a much lesser extent, as a partial agonist of the 5-HT_1A receptor (K_i = 414 nM; E_max = 54%).^{[2] [3]} It has negligible affinity for the dopamine D₂, D₃, and D₄ receptors (K_i > 10,000 nM) and does not appear to have significant affinity for the α₁-adrenergic receptors.^[4] Its crystal structure has been determined.^[5]

Derivatives

A number of pyrimidinylpiperazine derivatives are drugs, including:

• Buspirone anxiolytic
• Dasatinib anticancer agent
• Eptapirone anxiolytic
• Gepirone anxiolytic
• Ipsapirone anxiolytic
• Piribedil antiparkinsonian agent
• Revospirone anxiolytic
• Tandospirone anxiolytic
• Tirilazad neuroprotective agent
• Umespirone anxiolytic
• Zalospirone anxiolytic

The anxiolytics are also classified as azapirones due to the azaspirodecanedione moiety in their structures. 1-PP is a common metabolite of most or all of the listed agents.^[6] Alnespirone, binospirone, and enilospirone, despite being azapirones, are not piperazines and therefore do not metabolize to 1-PP, and while perospirone and tiospirone are piperazines, they are instead benzothiazole-substituted piperazines and do not metabolize to 1-PP either.

See also

• Substituted piperazine
• Pyridinylpiperazine
• Phenylpiperazine
• Diphenylmethylpiperazine
• Benzylpiperazine

Notes and References

1. Blier P, Curet O, Chaput Y, de Montigny C . Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission . Neuropharmacology . 30 . 7 . 691–701 . 1991 . 1681447 . 10.1016/0028-3908(91)90176-c. 44297577 .
2. Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M . Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats . J. Pharmacol. Exp. Ther. . 303 . 3 . 1130–7 . 2002 . 12438536 . 10.1124/jpet.102.036798 . 14139919 .
3. Gobert. A.. Newman-Tancredi. A.. Rivet. J.M.. Audinot. V.. Millan. M.J.. P.1.047 Yohimbine is a potent, partial agonist at rat and cloned, human serotonin1A receptors: A comparison to buspirone and its metabolite, 1-pyrimidinylpiperazine. European Neuropsychopharmacology. 7. 1997. S149–S150. 0924-977X. 10.1016/S0924-977X(97)88496-9. 54355225.
4. Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P . Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors . Int. J. Neuropsychopharmacol. . 16 . 2 . 445–58 . 2013 . 22827916 . 5100812 . 10.1017/S1461145712000661 .
5. Yamuna . T. S. . Jasinski . J. P. . Kaur . M. . Anderson . B. J. . Yathirajan . H. S. . Crystal structures of 4-(pyrimidin-2-yl)piperazin-1-ium chloride and 4-(pyrimidin-2-yl)piperazin-1-ium nitrate . Acta Crystallographica Section E: Structure Reports Online . 1 October 2014 . 70 . 10 . 203–206 . 10.1107/S1600536814020169. 25484652 . 4257175 . 2014AcCrE..70..203Y .
6. Astier B, Lambás Señas L, Soulière F, Schmitt P, Urbain N, Rentero N, Bert L, Denoroy L, Renaud B, Lesourd M, Muñoz C, Chouvet G . In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity . Eur. J. Pharmacol. . 459 . 1 . 17–26 . 2003 . 12505530 . 10.1016/s0014-2999(02)02814-5.