Lipolytic action of a new alpha-2 adrenergic antagonist of the piperazinopyrimidine family: RP 55462.
Recent investigations have demonstrated the in vitro lipid mobilizing effects induced by alpha-2 adrenergic antagonist administration and have focused attention on the putative therapeutic interest of such compounds in the treatment of obesity as adjuvants in caloric restriction programs. We studied the impact of RP 55462 [6-chloro-4-(isopropylamino)-5-(methyl)-2, piperazinopyrimidine], a new alpha-2 adrenergic antagonist compound of the piperazinopyrimidine family, on fat cell function. The alpha-2-blocking properties of this agent, which had been defined initially on the brain were confirmed on adipocytes. RP 55462 competed with [3H]yohimbine binding sites on human fat cell membranes and inhibited the antilipolytic action of alpha-2-agonist compounds (UK 14304, clonidine and epinephrine) in human and hamster fat cells. It was also noticed that RP 55462 alone was able to activate lipolysis in isolated fat cells from various species (man, rat, hamster and dog). Moreover, the lipolytic response induced by isoproterenol or synacthene was largely amplified in the presence of RP 55462 in rat fat cells which are the least alpha-2 adrenergic responsive tested. RP-55462-dependent stimulation of lipolysis was not affected by the presence of other alpha-2 adrenergic antagonists (idazoxan, yohimbine or phentolamine). Intravenous administration of RP 55462 in alert dogs promoted an increment in plasma nonesterified acid concentrations reflecting its lipid mobilizing action. In summary this study focuses attention on a new alpha-2-antagonist compound which exhibits an in vivo lipid mobilizing action which could be attributable to its alpha-2 adrenergic antagonist properties. Inasmuch as the lipolytic activity of RP 55462, revealed in in vitro studies, seems to be independent from its alpha-2 adrenolytic properties; further studies are required to define the mechanism of such a lipolytic effect as well as its possible involvement in in vivo conditions.
Saulnier-Blache
J S
JS
Institut National de la Santé et de la Recherche Médicale U-317, Université Paul Sabatier, Toulouse, France.
Taouis
M
M
Dauzats
M
M
Uzan
A
A
Berlan
M
M
Lafontan
M
M
D000243:Adenosine Deaminase / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D006224:Cricetinae; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008053:Lipid Mobilization / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015016:Yohimbine / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D005230:Fatty Acids, Nonesterified; D010879:Piperazines; D011743:Pyrimidines; C062149:RP 55462; D015016:Yohimbine; D000243:Adenosine Deaminase