PTIQ

A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP.[Pubmed:21951056]

Br J Pharmacol. 2012 Apr;165(7):2213-27.

BACKGROUND AND PURPOSE: In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation. EXPERIMENTAL APPROACH: We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated. KEY RESULTS: PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1beta, TNF-alpha and cyclooxygenase-2 and blocked nuclear translocation of NF-kappaB. In the mouse model of Parkinson's disease ,induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg(-1) and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection. CONCLUSIONS AND IMPLICATIONS: These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.

Studies on the mechanism of action of 1-(2-methyl-3-hydroxy-5-hydroxy-methyl-4-pyridyl)-6,7-dihydroxy-1,2,3, 4- tetrahydroisoquinoline (PTIQ) on blood pressure in the anesthetized dog.[Pubmed:2781139]

Res Commun Chem Pathol Pharmacol. 1989 Jun;64(3):421-33.

The mechanism of action of PTIQ in lowering the arterial blood pressure in the anesthetized dog was studied using pharmacological and physiological techniques. The hypotensive activity of PTIQ was significantly inhibited by pretreatment with bilateral vagotomy, propranolol, prazosin and mecamylamine. Pretreatment with either yohimbine or reserpine had no significant effect on PTIQ activity. PTIQ produced a significant decrease in the force of contraction of myocardial tissue and a transient increase in the aortic blood flow of the anesthetized dog. These results indicate a multiplicity of action of PTIQ in controlling arterial blood pressure.

Syntheses of tetrahydroisoquinoline derivatives that inhibit NO production in activated BV-2 microglial cells.[Pubmed:17980460]

Eur J Med Chem. 2008 Jun;43(6):1160-70.

Seventeen tetrahydroisoquinoline derivatives were designed, synthesized and evaluated for inhibition of NO production in lipopolysaccharide-stimulated BV-2 microglial cells. Compounds 5a, 9c and 11a potently attenuated NO production by >60%, and 5a and 11a inhibited BH4 production by >48% at 100 microM. In particular, N-ethylcarbonyl-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (11a) reduced NO production by 64% and tetrahydrobiopterin (BH4) production by 49%. Introducing longer alkyl component at C1 or N2 position led to attenuation of the inhibitory effect. It is possible that 11a inhibits NO production by blocking BH4-dependent dimerization of newly synthesized iNOS monomers.