A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.
The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.
Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Magdalena
M
Dudek
Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Joanna
J
Knutelska
Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Marek
M
Bednarski
Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Leszek
L
Nowiński
Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Małgorzata
M
Zygmunt
Department of Pharmacobiology, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Barbara
B
Mordyl
Department of Pharmacobiology, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Monika
M
Głuch-Lutwin
Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Grzegorz
G
Kazek
Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Jacek
J
Sapa
Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.
Karolina
K
Pytka
D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D016316:Guanfacine / Q000008:administration & dosage* / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008024:Ligands; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D014481:United States; D015016:Yohimbine / Q000008:administration & dosage* / Q000009:adverse effects
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D001067:Appetite Depressants; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D016316:Guanfacine