Alkylating prazosin analogue: irreversible label for alpha 1-adrenoceptors.

A series of prazosin analogues comprised of N-acyl derivatives of N'-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazine was prepared and the nature of their binding to alpha 1-adrenoceptors was investigated. Derivatives with alpha, beta-unsaturated acyclic acyls had some affinity but no irreversible action at the receptor. Other potent compounds, also without irreversible activity, contained cinnamoyl or (phenylamino)thiocarbonyl residues. High affinity and irreversible binding were obtained with a bicyclo[2.2.2]octa-2,5-dien-2-ylcarbonyl derivative. The conjugated double bond in this compound was in about the same position and distance from the pharmacophore as in some of the above compounds of high affinity but with no irreversible action. Two consecutive recognition steps were thought to be involved in irreversible blockade: reversible binding of the pharmacophore part of the molecule to the binding site of the receptor, followed by reaction of the chemoreactive part with an adjacent nucleophile of the receptor. The present results suggest that for the second step to occur efficiently, some affinity for the receptor must be present even in the chemoreactive part of the molecule; simple spanning of the binding and nucleophile sites of the receptor was insufficient.