Eric C. Bigham

α1-Adrenoceptor Agonists: The Identification of Novel α1A Subtype Selective 2′-Heteroaryl-2-(phenoxymethyl)imidazolines

Abstract Novel 2′-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human α 1 -adrenoceptors in vitro. The nature of the 2′-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. α 1A Subtype selective agonists have been identified.

α1-Adrenoceptor activation: A comparison of 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles to related 2-imidazolines

Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and alpha(1)-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate alpha(1)-adrenoceptors.

Multisubstrate Analogue Inhibitors of Glycinamide Ribonucleotide Transformylase Based on 5-Deazaacyclo Tetrahudrofolate (5-DACTHF)

N 10 -Substituted acetyl derivatives of 5-DACTHF are less active in general than the parent. However, multisubstrate analogue inhibitors that are 1000-fold more potent were synthesized, and N 10 -pyruvoyl-5-DACTHF serves as a precursor for a metabolically assembled multisubstrate analogue

On the substrate specificity of bovine liver dihydrofolate reductase: new unconjugated dihydropterin substrates.

The substrate specificity of dihydrofolate reductase from cells of different origin has been thought to be quite narrow, and unconjugated dihydropterins such as 6-methyl-dihydropterin are known to be very poor substrates. We have reinvestigated the substrate specificity of several dihydropterins and, in addition, have observed that in a new series of unconjugated dihydropterins of the general structure 6-CH2O(CH2)nCH3 several compounds are excellent substrates for the bovine liver enzyme, but none of them bind as well as dihydrofolate. The substrate activity (apparent Vmax) of these compounds increases from 17 to 110% that of the natural substrate, dihydrofolate, as n is increased from 0 to 3. In contrast, these unconjugated dihydropterins are very poor substrates for the Escherichia coli enzyme.