Stimulation of insulin secretion by imidazoline compounds is not due to interaction with non‐adrenoceptor idazoxan binding sites

Abstract

efaroxan and RX821002, which are related in structure to idazoxan, were much less effective as displacers. 4 In insulin secretion experiments, the ATP-sensitive potassium channel agonist diazoxide (250 ftM) was able to suppress the rise in insulin secretion induced by 20 mM glucose. Both efaroxan and RX821002 (100 ELM) antagonized the inhibitory effect of diazoxide on glucose-induced insulin secretion. By contrast, neither idazoxan (100 M) nor UK14304 (50 gM), was able to overcome significantly the inhibitory effect of diazoxide. 5 The ability of 100 m efaroxan to antagonize the suppression of insulin secretion mediated by diazoxide, was not prevented by idazoxan (up to 100 M) or by UK14304 (up to 50 pM). 6 The results indicate that the stimulatory effects of imidazoline compounds on insulin secretion are not due to interaction with NAIBS similar to those present in rat liver.

The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I1‐ and I2‐sites

“…Moreover, RX821002 was also able to antagonize the inhibitory effect of diazoxide on glucose-induced insulin secretion (Table 1). These data confirm previous studies suggesting that the mechanism of action of imidazoline compounds involves interaction with a regulatory component associated with ATP-sensitive potassium channels (Plant & Henquin, 1990;Chan & Morgan, 1990;Chan, 1993 whereas idazoxan and UK14,304 do not augment insulin secretion (Chan et al, 1988;Schulz & Hasselblatt, 1989b;Chan & Morgan, 1990;Brown et al, 1993 a-cells (Plant & Henquin, 1990;Chan, 1993). As yet, the nature of the binding site mediating this effect has not been disclosed.…”

“…Similarly, the capacity of phentolamine to antagonize the inhibitory effects of diazoxide was also impaired in these islets ( Figure lb). Conversely, culture of islets in the presence of either idazoxan (Figure lc) or UK14,304 (Figure Id), imidazoline ligands (12-site) which do not stimulate insulin release (Chan & Morgan, 1990;Chan et al, 1991b;Brown et al, 1993), did not lead to any loss of response when the islets were subsequently exposed to efaroxan or phentolamine.…”

Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080

“…[3H]-idazoxan will label non-adrenoceptor sites in rat islets and cultured P-cell lines (Remaury & Paris, 1992), it neither stimulates insulin secretion nor antagonizes the effects of other imidazolines in rat islets (Chan & Morgan, 1990;Brown et al, 1993). Thus, it appears that the functionally important binding site for imidazolines in islets differs from those described previously in other tissues, and that [3H]-idazoxan is not a suitable ligand with which to label this site.…”

“…This site does not appear to belong to either of the recently designated I, or 12 subclasses of 'imidazoline receptor' (although such sites may be present on islet cells (Remaury & Paris, 1992;Brown et al, 1993)) since it appears to have very low affinity for idazoxan . However, the putative 'imidazoline binding site' responsible for control of K-ATP channel activity in the P-cell shows stereoselectivity and the response is subject to downregulation by agonists, suggesting that the binding site may represent a new type of imidazoline receptor (Chan et al, 1993).…”

Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type II Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4‘,5‘-dihydro-1‘H- imidazol-2‘-yl)piperazines and Isosteric Analogues of Imidazoline

“…This is in agreement with an increasing number of studies showing that R 2 adrenergic antagonists are able to stimulate insulin secretion independently of R 2 and I 1 , I 2 blockage. 16,17,28,29,[31][32][33][34][35][36][37][38] …”