Pharmacological characterization of (3-thienylidene)-3,4-methylenedioxybenzoylhydrazide: a novel muscarinic agonist with antihypertensive profile.
BACKGROUND
Several new bioactive compounds of the N-acylhydrazone class were developed from the safrole, a Brazilian natural product obtained from sassafras oil (Ocotea pretiosa). This work investigated the effects on cardiovascular system of LASSBio-897, a new analogue of the lead compound 3,4-methylenedioxybenzoyl-2-thienylhydrazone named LASSBio-294.


METHODS
Thoracic aorta from Wistar-Kyoto (WKY) rats was prepared for isometric tension recording and for cGMP content determination. Blood pressure (BP) was measured in WKY rats and spontaneously hypertensive rats (SHR) after treatment with 1 mg/kg intravenously of LASSBio-897 and during 14 days' treatment of SHR with 1 mg/kg/day perorally.


RESULTS
LASSBio-897 (0.05-1 micromol/l) exhibited a potent vasodilatory activity in phenylephrine (Phe)-contracted aortic rings from WKY rats. This effect was abolished in endothelium-denuded aortic rings and after treatment with the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Also, LASSBio 897 (1 micromol/l) increased about 15 times the intracellular content of cGMP. LASSBio-897-induced vasodilation was totally inhibited by the muscarinic antagonist atropine and by the M(3) subtype selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), indicating the involvement of M(3) receptors. Intravenous administration of LASSBio-897 (1 mg/kg) produced significant hypotensive response in both WKY and SHR. The hypotensive effect of LASSBio-897 was also observed during the 14 days of oral administration.


CONCLUSIONS
The novel N-acylhydrazone derivative LASSBio-897 exhibited a potent vasodilatory activity in aortic rings mediated by the NO/cGMP pathway via activation of endothelial M(3) receptors and was orally effective in reducing BP on SHR.
Zapata-Sudo
Gisele
G
Programa de Desenvolvimento de Fármacos, Departamento de Farmacologia Basica e Clinica, ICB, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Pereira
Sharlene L
SL
Beiral
Hellen J V
HJ
Kummerle
Arthur E
AE
Raimundo
Juliana M
JM
Antunes
Fernanda
F
Sudo
Roberto T
RT
Barreiro
Eliezer J
EJ
Fraga
Carlos A M
CA
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011976:Receptors, Muscarinic / Q000187:drug effects; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
C547574:(3-thienylidene)-3,4-methylenedioxybenzoylhydrazide; D000959:Antihypertensive Agents; D052117:Benzodioxoles; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D013876:Thiophenes; D006152:Cyclic GMP