Structure-Activity Study of LVV-Hemorphin-7: Angiotensin AT₄ Receptor Ligand and Inhibitor of Insulin-Regulated Aminopeptidase

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Independent studies demonstrated that a hemoglobin b-chain fragment isolated from sheep brain with a sequence, LeuVal-Val-hemorphin-7 (LVV-H7) is also capable of binding and activating the in vivo physiologic effects attributed to activation of putative AngIV binding sites (Moeller et al, 1997). The distribution of 125 I-LVV-H7 binding sites in brain slices was identical to those for [ 125 I]AngIV, suggesting that it is an endogenous AngIV binding site ligand (Moeller et al, 1997(Moeller et al, , 1998Lee et al, 2001Lee et al, , 2003.…”

“…Exogenous administration of AngIV has been shown to increase cerebral microcirculation (Naveri et al, 1994;Kramar et al, 1997;Kramar et al, 1998;Lanckmans et al, 2007a,b). In terms of function, intracranially administered AngIV and its functional analogs facilitate memory in rodent behavior models (Braszko et al, 1988;Wright et al, 1993;Tchekalarova et al, 2001;Lee et al, 2003). AngIV also facilitates reversal of memory shortfalls produced by scopolamine, mecamylamine, abusive alcohol dose, ischemia, as well as by disruption of the perforant path in the hippocampus (Borawska et al, 1989;Wright et al, 1996;Pederson et al, 1998;Albiston et al, 2004a;Olson et al, 2004).…”

Phenylalanine-544 Plays a Key Role in Substrate and Inhibitor Binding by Providing a Hydrophobic Packing Point at the Active Site of Insulin-Regulated Aminopeptidase

“…Peptidomimetic approaches have developed further inhibitors of the enzyme (Axén et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009, predominantly Ang IV analogs with increased stability, but without significant improvement in affinity for IRAP. A tyrosine near the N terminus of the peptide inhibitors is a key amino acid residue for both Ang IV (Tyr 2 ) and LVV-H7 (Tyr 4 ); alanine substitution of this amino acid results in complete loss of binding to IRAP (Sardinia et al, 1993;Lee et al, 2003). Specificity is an issue with these peptide inhibitors of IRAP because they are able to bind to aminopeptidase N (APN) and the G-protein-coupled receptors, in addition to angiotensin AT 1 and the opioid receptors, at micromolar concentration (Demaegdt et al, 2006).…”

The brain angiotensin IV/AT4 receptor system as a new target for the treatment of Alzheimer's disease

“…Several observations and research findings are relevant: (1) The highest brain levels of AT 4 receptors are in the neocortex, piriform cortex, hippocampus, amygdala, and nucleus basalis of Meynert, consistent with a role in cognitive processing [Chai et al, 2000;Gard, 2002;Harding et al, 1992;Wright et al, 2008]; (2) the ability of the AT 4 subtype to facilitate LTP, separate from NMDA-dependent LTP, suggests a non-glutamatergic signaling pathway ; (3) activation of AT 4 receptors increases calcium internalization via at least three different calcium channels suggesting a rapid and salient cell signaling event ; (4) conversion of AngII to AngIV appears necessary for AngII-induced DA release in striatum [Stragier et al, 2004] and ACh release in the hippocampus [Lee et al, 2003]; (5) coupling of increased neural intracellular calcium, with matrix metalloproteinases released into the extracellular space, may imply a role in neural plasticity [Meighan et al, , 2007; (6) neural imaging Table 1 for details of the testing protocol. On each training day, rats in all 5 groups were pretreated with intracerebroventricular (icv) scopolamine (Scop, 70 nmol in 2 ml artificial cerebrospinal fluid [aCSF]) 20 min prior to training, followed by the analog (icv dose of 1 nmol in 2 ml aCSF) given 5 min prior to training.…”