In-vivo effects of the 1,2,4-piperazine derivatives MM5 and MC1, putative 5-HT agonists, on dopamine and serotonin release in rat prefrontal cortex.
Two 1,2,4-substituted derivatives of piperazine were tested for their effect on dopamine and serotonin (5-HT) release in rat prefrontal cortex. Both compounds, 1-[4-(4-chinolin-2-yl-piperazin-1yl)-butyl]piperidin-2-on (MM5) and 1-[4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl]-8-azaspiro [4.5]decano-7,9-dion (MC1), produced hypothermia in mice and showed affinity for 5-HT1A receptors in-vitro. Like the selective 5-HT1A agonist 8-OH-DPAT (0.1 mg kg(-1)), MM5 given peripherally (30 mg kg(-1)) decreased the extracellular 5-HT level in rat prefrontal cortex, while MC1 suppressed 5-HT release at a higher dose (40 mg kg(-1)), but not at a lower one (30 mg kg(-1)). The effect of both compounds on 5-HT release was abolished by WAY 100635 (0.3 mg kg(-1)). MC1 (30 and 40 mg kg(-1)), but not MM5, raised cortical dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and extracellular homovanillic acid (HVA) levels. The effect of MC1 on dopamine release was reversed by neither WAY 100635 nor the non-selective 5-HT2 antagonist ritanserin (2 mg kg(-1)). However, ritanserin prevented the effect of the higher dose of MC1 on 5-HT release. The results of this study suggest that MM5 exhibits the profile of a 5-HT1A agonist devoid of dopaminergic activity. MC1 seems to possess moderate agonist activity at 5-HT1A and 5-HT2A receptors, while acting on 5-HT release in the rat prefrontal cortex. However, the facilitation of dopamine release by this compound does not seem to be related to its affinity for 5-HT1A and 5-HT2A receptors.
Iskra-Jopa
Joanna
J
Pharmaceutical Research Institute, Rydygiera 8, PL-01-793 Warszawa, Poland.
Gołembiowska
Krystyna
K
Dziubina
Anna
A
Cybulski
Marcin
M
Duszyńska
Beata
B
Chilmonczyk
Zdzisław
Z
D015102:3,4-Dihydroxyphenylacetic Acid / Q000737:chemistry / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000737:chemistry / Q000502:physiology*; D045604:Extracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000737:chemistry / Q000378:metabolism; D008297:Male; D017551:Microdialysis / Q000379:methods; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010881:Piperidones / Q000378:metabolism / Q000494:pharmacology*; D011044:Poland; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000502:physiology; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000737:chemistry / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C503602:1-(4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl)-8-azaspiro (4.5)decano-7,9-dione; C503603:1-(4-(4-chinolin-2-yl-piperazin-1yl)-butyl)piperidin-2-one; D010879:Piperazines; D010881:Piperidones; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D013141:Spiro Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D044282:Receptor, Serotonin, 5-HT1A; D016713:Ritanserin; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D004298:Dopamine; D006719:Homovanillic Acid