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.
D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011224:Prazosin / Q000378:metabolism; D011719:Pyrazines / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*
D011719:Pyrazines; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D003000:Clonidine; D011224:Prazosin