Mechanism of lipolytic action of a new alpha-2 adrenergic antagonist of the piperazinopyrimidine family: RP 55462.
The in vivo lipid mobilizing effect of alpha-2 adrenergic antagonist has been demonstrated previously. This has attracted attention to the putative interest of such compounds in a lipid-mobilizing strategy. RP 55462 [6-chloro-4-(isopropylamino)-5-(methyl)-2 piperazinopyrimidine], a piperazinopyrimidine derivative, has already been shown to exert alpha-2 adrenergic antagonist actions on fat cell function in vitro. Moreover, RP 55462 exhibits a direct in vitro lipolytic action which is independent of its alpha-2-blocking potency. When administered i.v. RP 55462 is also able to induce an increment in plasma nonesterified levels in dogs. The mechanism of action of RP 55462 was studied and the nature of its lipomobilizing effect was explored. RP 55642-dependent lipolysis was not affected by beta adrenergic blockers on rat fat cells and RP 55462 had no direct effect on adenylylcyclase activity on fat cell membranes. Moreover, RP 55462 did not compete with [3H]phenyl isopropyl adenosine binding (A1-adenosine receptor agonist) on fat cell membranes. In fact, RP 55462 inhibited, in a dose-dependent manner, the cyclic AMP (cAMP)-dependent phosphodiesterase (PDE) activity in rat adipose tissue. Several derivatives with the piperazinopyrimidine structure also inhibited cAMP-dependent PDE activity and exerted lipolytic effects. A short structure-activity study was performed with various derivatives. In dogs, by contrast with yohimbine, the in vivo lipid mobilizing effect of RP 55462 was not abolished by pretreatment with propranolol, and lasted longer. It is concluded that the in vivo lipolytic activity of RP 55462 is connected with its ability to inhibit cAMP-dependent PDE activity; a property of several piperazinopyrimidine derivatives. The lipid mobilizing effect induced in vivo by RP 55462 results from a combination of its alpha-2 adrenergic antagonist properties and its direct lipolytic action mediated by cAMP-dependent PDE inhibiting effects.
Saulnier-Blache
J S
JS
Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier, Toulouse, France.
Taouis
M
M
Dauzats
M
M
Uzan
A
A
Berlan
M
M
Lafontan
M
M
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000032:analysis; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D006224:Cricetinae; D004285:Dogs; D066298:In Vitro Techniques; D008053:Lipid Mobilization / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D010879:Piperazines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011983:Receptors, Purinergic / Q000187:drug effects; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011743:Pyrimidines; D011943:Receptors, Adrenergic, beta; D011983:Receptors, Purinergic; C062149:RP 55462; D011433:Propranolol; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine