Neuropeptide Y (NPY) Y₄Receptor Selective Agonists Based on NPY(32−36):  Development of an Anorectic Y₄Receptor Selective Agonist with Picomolar Affinity

Abstract

We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y(4) receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-d/l-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y(4) selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y(4)(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y(4) receptors.

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

“…Importantly, our 30-min time point used throughout these studies is earlier than time points at which physiological responses to PP have been observed. For instance, PP has been shown to significantly reduce food intake when measured at 1 or 2 and 4 (Balasubramaniam et al, 2006) h after i.p. administration.…”

“…We have previously shown that PP dose-dependently reduces food intake in freely fed and fasted mice and this effect was mediated through the Y4 receptor as it was completely abolished in Y4 receptor knockout mice (Balasubramaniam et al, 2006). To determine whether the LHA and/or the VMH may be involved in PP's effects on food intake and to map the neuronal pathways concerned, we investigated the expression of the early neuronal marker c-Fos in response to peripherally-injected PP.…”

“…PP dose-dependently reduces food intake in freely fed and fasted mice, and this is mediated through the Y4 receptor since the effect is abolished in Y4 receptor knockout mice (Balasubramaniam et al, 2006 andLin et al, 2009).…”

Role of gastrointestinal hormones in feeding behavior and obesity treatment

“…Many studies have shown that PP decreases food intake with a delay of gastric emptying after peripheral administration in humans and rodents [105][106][107]. PP can interact with all subtypes of the Y receptor family, while it has the highest affinity toward Y4 receptors, particularly in the VMN, PVN, AP, and ARC [107][108][109].…”

Gastrointestinal hormones, energy balance and bariatric surgery

“…18,19 By contrast, the neurons in the lateral ARC coexpress proopiomelanocortin (also known as corticotropin-lipotropin) and cocaine-and amphetamineregulated transcript, which both promote weight loss by decreasing appetite. 20,21 Both the ARC and the brainstem are ideally positioned to interact with circulating humoral factors and to receive signals from the periphery. 22,23 Thus, gut hormones may function directly in the brain after being released into the circulation and signaling through circumventricular organs.…”