P3-agonists

Himms-Hagen J, Cui J, Danforth E Jr, et al. Effect of CL-316,243, a thermogenic P3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol 1994 266 R1371-R1382. 

In relation to the substitution reaction of the 1,2-ketal 47, the reaction of 1,2-dibutyroyl inositol 72 with 1.1 equiv of butyric anhydride in pyridine was found to give predominantly the 3-0-acylation product 73 in 50% yield together with smaller amounts of 74 and 75. 0 One product 74 was used to prepare racemic 2,3,6-tri-O-butyroyl-myo-inositol 1,4,5-trisphosphate, which was proved to be a membrane-permeant Ins(l,4,5)P3 agonist (Scheme 3-8). 

The syntheses of racemic 2-deoxy-2-fluoro-m> o-inositol 1,4,5-triphosphate and of 2-deoxy-2-fluoro-scy//o-inositol 1,2,4-triphosphate as novel Ins(l,4,5)P3 agonists using the intermediate triflate 116 have been reported. 

P3-adrenergic receptor Altered leptin and insulin concentrations after agonist treatment [66]... 

Ugarte, S. D., Homanics, G. E Firestone, L. L and Hammond, D. L. (2000) Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the P3 subunit of the GABAa receptor. Neuroscience 95,795-806. 

Basal levels of Ca2+ in resting neutrophils are around 100 nM. Upon stimulation with soluble agonists such as fMet-Leu-Phe, PAF and LTB4, intracellular levels rise to about 1 pM within 20-30 s and then return to basal levels. Experiments in which neutrophils are suspended in media devoid of Ca2+ (and containing EGTA to chelate trace contaminants of this cation), show that although the initial rise in intracellular Ca2+ is unaffected, the elevation in concentration is not sustained when extracellular Ca2+ is absent. Thus, the initial rise in intracellular Ca2+ is due to mobilisation of intracellular stores Ca2+ influx is then activated in order to sustain these levels (Fig. 6.11). Addition of Ins 1,4,5-P3 to permeabilised neutrophils results in a rapid (within 2 s) rise in intracellular Ca2+, which then declines to basal levels, possibly as a result of the released Ca2+ returning to the intracellular stores. These intracellular vesicles must therefore have independent Ca2+ efflux and influx. 

The role of Gpy, released from pertussis toxin-sensitive G proteins, in coupling activated receptor to effectors further complicates specificity. Delta opioids activate G protein-coupled inwardly rectifying K+ channels [50] activation of such channels occurs by direct binding of Gp-y to various regions of the channel [51]. Delta agonist-mediated increase in the release of Ca2+ from intracellular stores in NG108-15 cells is mediated by Gp-y subunits [52], and Gp antibodies inhibited DPDPE stimulated PLC-p activation and, therefore, Ins(l,4,5)P3-dependent Ca2+ release and smooth muscle contraction in intestinal smooth muscle cells of the guinea pig [46]. However, the Ga... 

P3. Pampfer, S., Vankrieken, L., Loumaye, E., De Hertogh, R., and Thomas, K., Inhibin and renin in follicular fluids of patients with one or two ovaries stimulated with a GnRH agonist and gonadotrophins. Hum. Reprod. 4, 396-402 (1989). 

BaNNO Y, NAKASHIMA T, HasHIYA T, NOZAWA Y. Endogenous deavage of phospholipase C-P3 by agonist-induced activation of calpain in human platdets. JBiol Chem 270 4318-4324,1995. 

The initial high levels of IP3 in response to agonist-receptor interaction are not maintained during the sustained phase of contraction (Chilvers et al, 1989 Chilvers and Nahorski, 1990). IP3 fells to baseline levels within a minute of the onset of contraction. I(1,4,5)P3 is metabohzed by two pathways, both of which are activated by increases in cytosolic Ca " hydrolysis by a 5-phosphatase enzyme to I(1,4)P2, or phosphorylation to I(1,3,4,5)P4 and subsequent hydrolysis to its inactive isomer I(1,3,4)P3 (Chilvers and Nahorski, 1990). No physiological role for I(1,3,4,5)P4 has yet been identified in airway smooth muscle, although in other cells evidence exists that I(1,3,4,5)P4 may modulate plas-malemmal Ca ion channels (Irvine and Moor, 1986). The only phosphoinositide metabolite which has been shown to release stored Ca in ASM is I(1,4,5)P3. 

Tavernier G, Galitzky J, Bousquetmelou A, Montastruc JL, Berlan M. The positive chronotropic effect induced by BRL-37344 and CGP-12177,2 P3 adrenergic agonists, does not involve cardiac p-adrenoceptors but baroreflex mechanisms. J Pharmacol Exp Therl992 263 1083-1090. 

---