New beta-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies.
Clenbuterol and beta-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named 'A' and 'G4', found in feeding stuffs. Chemical structure was studied through nuclear magnetic resonance-imaging and infrared spectroscopy, and beta(1)- and beta(2)-adrenergic activity was evaluated on isolated guinea-pig atrium and trachea in comparison with clenbuterol. Both compounds share with clenbuterol an halogenated aromatic ring with a primary amino group. Main modifications consisted of substitution of secondary amino group with an alkyl chain in compound A and substitution of the ter-butyl group with a benzene ring in compound G4. In guinea-pig trachea these compounds showed myorelaxant potency lower than clenbuterol (EC(50) was 43.8 nM for clenbuterol, 11700 nM for compound A, 2140 nM for G4). On the contrary, in the guinea-pig atrium (heart-beat rate stimulant effect) the compounds were more potent than clenbuterol (EC(50) was 15.2 nM for clenbuterol, 3.4 nM for compound A, 2.8 nM for G4). These pharmacodynamic properties, and stronger lipophilic properties shown by the two compounds may result in increased cardiovascular risk for consumers of illicitly treated animals.
Mazzanti
Gabriela
G
Dipartimento di Farmacologia delle Sostanze Naturali e Fisiologia Generale, University of Roma La Sapienza, P.zale Aldo Moro, Italy. gabriela.mazzanti@uniroma1.it
Daniele
Claudia
C
Boatto
Gianpiero
G
Manca
Giuliana
G
Brambilla
Gianfranco
G
Loizzo
Alberto
A
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000821:Animal Feed / Q000009:adverse effects*; D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001947:Breeding; D002976:Clenbuterol / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005559:Formamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013610:Tachycardia / Q000139:chemically induced; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001555:Benzene Derivatives; D005559:Formamides; C474484:N-(2,6-dichloro-4-(2-oxiacetyl)phenylformamide); D011943:Receptors, Adrenergic, beta; C474485:compound G4; D002976:Clenbuterol