Piperazinylimidazo[1,2-a]pyrazines with selective affinity for in vitro alpha-adrenergic receptor subtypes.

Regioselective syntheses of alkyl- and halogen-substituted piperazinylimidazo[1,2-a]pyrazines by novel oxidation-dehydration of [(beta-hydroxyalkyl)amino]pyrazines are described. Lanthanide shift reagent studies allowed correction of literature assignments of NMR chemical shifts and coupling constants for the imidazo[1,2-a]pyrazine ring system (e.g., J5,8 greater than J6,8). Equilibrium constants for displacement of specifically bound [3H]clonidine and [3H]prazosin from calf cerebral cortex homogenates in vitro are tabulated for reference and title compounds, and structure-affinity relationships for alpha 2- vs. alpha 1-adrenergic receptors are considered. Compound 2a, 8-(1-piperazinyl)imidazo[1,2-a]pyrazine, is equipotent with mianserin on the clonidine receptor (alpha 2) but ca. 70 times as selective as mianserin for this alpha 2-adrenergic receptor. Reduction of the imidazo ring (2,3-dihydro) lowers affinity for the alpha 2 receptor without affecting alpha 1-receptor affinity. Computer-assisted molecular modeling techniques are applied to the estimation of conformational energies of 2a and its 5-position isomer in relation to the semirigid molecule mianserin.
AuthorsW C Lumma Jr, W C Randall, E L Cresson, J R Huff, R D Hartman, T F Lyon
JournalJournal of medicinal chemistry (J Med Chem) Vol. 26 Issue 3 Pg. 357-63 (Mar 1983) ISSN: 0022-2623 [Print] UNITED STATES
PMID6298426 (Publication Type: Journal Article)
Chemical References
  • Pyrazines
  • Receptors, Adrenergic
  • Receptors, Adrenergic, alpha
  • Clonidine
  • Prazosin
  • Animals
  • Binding, Competitive
  • Cattle
  • Cerebral Cortex (metabolism)
  • Clonidine (metabolism)
  • Magnetic Resonance Spectroscopy
  • Prazosin (metabolism)
  • Pyrazines (metabolism)
  • Receptors, Adrenergic (metabolism)
  • Receptors, Adrenergic, alpha (metabolism)

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