AC 187

Amylin is a 37-amino acid peptide co-secreted with insulin from pancreatic β-ells. The plasma concentration of amyline increases with nutrient stimuli. AC187 is a potent amylin antagonist

In vitro: AC187 potently competes for rat amylin binding at high affinity sites such as rat nucleus accumbens membranes which have been useful in developing a number of selective ligands, including AC187. The Kd for amylin at this site is 28 pM, and the Ki for AC187 is 79 pM. AC187 is relatively selective in competing for amylin binding, displacing amylin from nucleus accumbens membranes with over 400-fold greater potency [1].

In vivo: AC187 was able to inhibit metabolic responses to exogenous amylin in the intact animal. An infusion of AC187 that was itself without effect on lactate levels in anesthetized rats, inhibited by more than 90% the lactate increment evoked by infusions of rat amylin. Other experiments have shown that AC187-induced amylin blockade action is surmountable by higher doses of amylin, indicative of a competitive antagonism [1].

Clinical trial: Up to now, AC187 is still in the preclinical development stage.

Reference:
[1] Young AA, Gedulin B, Gaeta LS, Prickett KS, Beaumont K, Larson E, Rink TJ.  Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat. Evidence for a metabolic role of endogenous amylin. FEBS Lett. 1994 May 2;343(3):237-41.

Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats.[Pubmed:15059694]

Physiol Behav. 2004 Mar;81(1):149-55.

According to previous studies, the area postrema (AP) of the hindbrain may play an important role in mediating the anorectic effect of the pancreatic hormone amylin. Peripheral amylin has been suggested to directly act on AP neurons to bring about its anorectic effect. Cyclic GMP may act as second messenger in this regard. In the present study, we wanted to further delineate the role of the AP in amylin's effect and to find out whether endogenous amylin might reduce feeding via the AP. Rats with chronic cannulas aiming at the AP were infused with various doses of amylin, its agonist salmon calcitonin (sCT) or a cyclic guanosine monophosphate (cGMP) analogue. Amylin and sCT inhibited food intake for about 2 h after food presentation, mainly by reducing meal size when infused into the AP [e.g., 1 h food intake after amylin (0.4 microg/rat) infusion in 12-h deprived rats: NaCl 4.0+/-0.5 vs. amylin 2.4+/-0.5, P<.05]. The effect was comparable in ad libitum fed and 12-h food-deprived rats with a minimal effective dose of 0.04 microg/rat. Similar to amylin and sCT, the cGMP analogue 8-Br-cGMP (200 nmol/rat) also reduced food intake and meal size. Infusion of the amylin antagonist AC 187 (30 microg) into the AP significantly reduced the anorectic effect induced by an intraperitoneal injection of amylin (5 microg/kg). Furthermore, AC 187 alone increased feeding when infused into the AP. This study is in line with previous work pointing to an important role of the AP in mediating the anorectic effect of amylin. Furthermore, we provide evidence for a physiological role of endogenous amylin to reduce food intake. This may also involve an action via the AP.

Chronic infusion of the amylin antagonist AC 187 increases feeding in Zucker fa/fa rats but not in lean controls.[Pubmed:15135020]

Physiol Behav. 2004 May;81(3):481-8.

Numerous studies have established the pancreatic B-cell hormone amylin as an important anorectic peptide affecting meal-ending satiety. In the present study, we investigated the effect of a chronic infusion of the amylin antagonist AC 187 on food intake. The studies were performed using obese Zucker fa/fa rats, which are hyperamylinemic but have a defective leptin and insulin signaling system. A chronic intraperitoneal infusion of the amylin antagonist AC 187 (10 microg/kg/h) significantly increased dark phase and total food intake in Zucker but not in lean control rats. During the 8-day infusion experiment, AC 187 had no clear effect on body weight gain in either group. After acute administration, amylin and its agonist salmon calcitonin (sCT) equally reduced food intake in Zucker and lean control rats while cholecystokinin's (CCK) anorectic effect was weaker in the Zucker rats. We provide evidence for amylin being a potential long-term regulator of food intake because AC 187 increased food intake in obese fa/fa rats but not in lean control animals, which have low baseline amylin levels. Amylin may play some role as lipostatic feedback signal similar to leptin and insulin at least when the leptin and insulin feedback signaling systems are deficient. Despite basal hyperamylinemia in the Zucker rats, they do not seem to be less sensitive to the anorectic effects of amylin or its agonist sCT than respective controls. This contrasts with CCK whose anorectic action is reduced in Zucker rats when compared with lean controls.

Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187.[Pubmed:16914214]

Regul Pept. 2006 Dec 10;137(3):121-7.

Amylin is a 37-amino acid polypeptide co-secreted with insulin from the pancreatic beta-cells. It complements insulin's stimulation of the rate of glucose disappearance (Rd) by slowing the rate of glucose appearance (Ra) through several mechanisms, including an inhibition of mealtime glucagon secretion and a slowing of gastric emptying. To determine if endogenous amylin tonically inhibits these processes, we studied the effects of the amylin receptor blocker AC187 upon glucagon secretion during euglycemic, hyperinsulinemic clamps in Sprague-Dawley (HSD) rats, upon gastric emptying in HSD rats, and upon gastric emptying and plasma glucose profile in hyperamylinemic, and genetically obese, Lister Albany/NIH rats during a glucose challenge. Amylin blockade increased glucagon concentration, accelerated gastric emptying of liquids, and resulted in an exaggerated post-challenge glycemia. These data collectively indicate a physiologic role for amylin in glucose homeostasis via mechanisms that include regulation of glucagon secretion and gastric emptying.

Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons.[Pubmed:15201330]

J Neurosci. 2004 Jun 16;24(24):5579-84.

Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloidbeta protein (Abeta) is one of the major, but still elusive, therapeutic goals of current research in Alzheimer's disease (AD). To date, no receptor has been unequivocally identified for Abeta. Human amylin, which acts via a receptor composed of the calcitonin receptor-like receptor and a receptor-associated membrane protein, possesses amyloidogenic properties and has a profile of neurotoxicity that is strikingly similar to Abeta. In this study, using primary cultures of rat cholinergic basal forebrain neurons, we show that acetyl-[Asn30, Tyr32] sCT(8-37) (AC187), an amylin receptor antagonist, blocks Abeta-induced neurotoxicity. Treatment of cultures with AC187 before exposure to Abeta results in significantly improved neuronal survival as judged by MTT and live-dead cell assays. Quantitative measures of Abeta-evoked apoptotic cell death, using Hoechst and phosphotidylserine staining, confirm neuroprotective effects of AC187. We also demonstrate that AC187 attenuates the activation of initiator and effector caspases that mediate Abeta-induced apoptotic cell death. These data are the first to show that expression of Abeta toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD.