Adrenal Steroidogenic Actions of Cyclic Nucleotide Derivatives in the Rat

Abstract

Fifteen 3',5'-cyclic nucleotides and related compounds were studied for ability to mimic the steroidogenic action of ACTH in rats in which secretion of ACTH and corticosterone were suppressed by treatment with betamethasone, or by hypophysectomy. Subcutaneous administration of 8-chloro-cAMP, at doses of 40 mg/kg or greater, elicited the secretion of corticosterone to normal plasma levels in both betamethasone-treated and hypophysectomized animals. Cyclic AMP, dbcAMP, 8-methylthio-cAMP, 8-hydroxy-cAMP and the 6-chloro-8-aminopurine cyclic ribotide analog of cAMP also displayed steroidogenic activity in the betamethasone-treated rat; cGMP, 8-bromo-cGMP and 8-benzylthio-cGMP were inactive. Each of the steroidogenic derivatives of cAMP also displayed ability to activate steroidogenesis in isolated rat adrenal cells. These experiments demonstrate that various derivatives of cAMP mimic the adrenal steroidogenic action of ACTH, in vivo. Structure-activity comparisons support a steroidogenic mechanism involving direct activation by the nucleotides of cAMP-dependent protein kinase of the adrenal cortex.

Characterization of the Hypothalamic-Pituitary-Adrenal Axis Response to Atrazine and Metabolites in the Female Rat

“…Additional studies indicate that ATR inhibits phosphodiesterase (Roberge et al, 2004(Roberge et al, , 2006; however, other signaling cascades, such as PI3K, are also altered (Suzawa and Ingraham, 2008). The ubiquitous nature and important function of these cellular signaling mechanisms throughout the body, including in GnRH neurons (Ojeda et al, 1988;Paruthiyil et al, 2002) and steroidogenic cells (Free and Paik, 1977), suggest that chlorotriazine-induced alterations of these intracellular pathways might influence a number of processes within multiple target tissues.…”

Synthesis and enzymic and ionotropic activity of some new 8-substituted and 6,8-disubstituted derivatives of adenosine cyclic 3',5'-monophosphate

“…An 8-substituted cAMP derivative, 8-chloro-cAMP,14 has recently been shown to mimic the adrenal steroidogenic action of ACTH in vivo.15 8-Chloro-cAMP elicited the secretion of corticosterone to normal plasma levels in both betamethasone treated and hypophysectomized rats. 15 The synthesis of additional 8-(alkylthio)-and 8-(arylthio)-cAMP derivatives described in the present work was prompted by the fact that 8-[ (p-chlorophenyl)thio] -cAMP16 (I) is 18 times more potent than cAMP16 as an activator of bovine brain cAMP-dependent protein kinase in vitro. 8-[(p-Chlorophenyl)thio] -cAMP (I) is 50 times more potent than dibutyryl-cAMP as an inducer of tyrosine aminotransferase in rat liver in vivo.17 I inhibits the 0-CHg d 0 = P-0 OH I OH I spontaneous firing of 92% of rat cerebellar Purkinje cells.…”