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At least 991 records · Page 55Linked to original sources
PubMed2007

Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates.

PURPOSE: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. METHODS: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. RESULTS: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT. CONCLUSION: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

Animals↗
PubMed1989

Astrocyte morphology altered by 1-(5-isoquinolinylsulfonyl) 2-methyl piperazine (H-7) and other protein kinase inhibitors.

Studies were conducted to determine if the protein kinase C inhibitor H-7 could block the effects of phorbol-12-myristate-13-acetate (PMA) on astrocyte morphology. Contrary to expectation, H-7 alone was found to induce morphological changes very similar to those elicited by PMA. This effect was shared by two other inhibitors of protein kinase C, H-8 and staurosporine, but not by the cyclic nucleotide-dependent protein kinase inhibitor HA-1004 or the calcium/calmodulin dependent protein kinase inhibitor W-7. Although the morphological effects observed with H-7 resemble those induced by PMA, H-7 did not promote the redistribution of protein kinase C to the membrane or induce the phosphorylation of endogenous proteins like PMA. In addition, the effects of H-7 were still observed in cells depleted of protein kinase C activity which were no longer responsive to treatment with PMA. Cytoskeletal elements appear to be involved in the effect of H-7 on cell shape since this effect is blocked by treatment with colchicine. Activators of the cyclic AMP-dependent protein kinase also alter astrocyte shape, however, while H-7 did cause a slight increase in cyclic AMP levels, it was unlikely that this action is responsible for its effect on morphology. One common action of both H-7 and PMA was to decrease the 32P content of several 20,000 Da proteins. While the mechanism by which H-7 exerts its influence on astrocyte morphology remains to be clarified, be it by the inhibition of protein kinase C or some other mechanism, the results suggest that caution must be used when interpreting the effects of activators and inhibitors of this kinase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1983

(1,2-Diphenylethyl) piperazines as potent opiate-like analgesics; the unusual relationships between stereoselectivity and affinity to opioid receptor.

A series of novel diphenylethylpiperazines were synthesized, and analgesic activities and opioid receptor interactions were evaluated. Analgesic activity of S(+) enantiomer of 1-cyclohexyl analogues (I-C6) was as potent as morphine. This compound showed narcotic properties. Racemate of I-C6 demonstrated the most potent analgesic activities among the enantiomorphic pairs. The R(-) isomer and (-) spa, NN-dimethyl-1, 2-diphenylethylamine, had mu-agonist like character. The S(+) isomer possessed high affinity for all types of the receptor, especially favorable for delta and kappa, in the different manner from opiate-like analgesics. It is conceivable that opioid receptor has various subsites, and this S(+) enantiomer alter the conformation of the receptor.

Analgesia↗
PubMed1993

Function specific supersensitivity of m-chlorophenyl piperazine-induced serotonergic neurotransmission in female compared to male rats.

Administration of various doses of m-chlorophenylpiperazine (m-CPP), a 5-hydroxytryptamine (5-HT) agonist, to rats increased plasma levels of corticosterone and decreased locomotor activity in a dose dependent manner. The increases of plasma corticosterone but not the decreases of locomotor activity were greater in female than male rats. Hypophagic effects of m-CPP not different in freely feeding male and female rats were greater in females when food deprived animals used. The findings along with our previous report show a functional supersensitivity of 5-HT neurotransmission involved in the regulation of hypothalamo-pituitary adrenocortical axis and appetite suppression in female sex, and suggest a possible basis for the greater occurrence of depression and anorexia in women than men.

Analysis of Variance↗