Delving into the Latest Updates on AC-187 with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

AC 187

Target

amylin

Mechanism

amylin inhibitors(Islet amyloid polypeptide inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetes Mellitus

Originator Organization

Bristol Myers Squibb Co. /Saint Nazaire Assets/

Active Organization-

Inactive Organization

Amylin Pharmaceuticals, Inc.Bristol Myers Squibb Co. /Saint Nazaire Assets/

Drug Highest PhaseDiscontinuedClinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC127H205N37O40

InChIKeyZLFXHYNEZYAYPG-AABHONRUSA-N

CAS Registry151804-77-2

Gene Sequence

Sequence Code 9130996

Recent findings have identified salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, as a potential regulator of alcohol-induced activation of the mesolimbic dopamine system and alcohol consumption. Providing that the role of amylin signalling in alcohol-related behaviours remains unknown, the present experiments investigate the effect of sCT on these behaviours and the mechanisms involved. We showed that repeated sCT administration decreased alcohol and food intake in outbred rats. Moreover, single administration of the potent amylin receptor antagonist, AC187, increased short-term alcohol intake in outbred alcohol-consuming rats, but did not affect food intake. Acute administration of sCT prevented relapse-like drinking in the "alcohol deprivation effect" model in outbred alcohol-experienced rats. Additionally, acute sCT administration reduced operant oral alcohol self-administration (under the fixed ratio 4 schedule of reinforcement) in selectively bred Sardinian alcohol-preferring rats, while it did not alter operant self-administration (under the progressive ratio schedule of reinforcement) of a highly palatable chocolate-flavoured beverage in outbred rats. Lastly, we identified differential amylin receptor expression in high compared to low alcohol-consuming rats, as reflected by decreased calcitonin receptor and increased receptor activity modifying protein 1 expression in the nucleus accumbens (NAc) of high consumers. Collectively, our data suggest that amylin signalling, especially in the NAc, may contribute to reduction of various alcohol-related behaviours.

01 Apr 2019·European journal of pain (London, England)

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Article

Author: Neto, Fani Lourença ; Almeida, Lígia Sofia ; Castro‐Lopes, José Manuel ; Potes, Catarina Soares

Abstract:

Background:

Amylin is a calcitonin gene‐related peptide family member expressed by nociceptors. Amylin's expression is down‐regulated following nerve damage, and studies suggested it affects nociception. We aimed at clarifying amylin's effects on chronic neuropathic pain and investigating its site of action.

Methods:

Chronic neuropathic pain was induced in rats by spared nerve injury (SNI) surgery. Mechanical allodynia/hyperalgesia and cold allodynia/hyperalgesia were assessed by the von Frey, pinprick, acetone and cold plate behavioural tests, respectively. Amylin, amylin‐receptor antagonist (AC187) or vehicle solutions were delivered chronically, by a subcutaneous (SC) mini‐osmotic pump, or acutely, by SC or intrathecal (IT) injections. Cellular and fibre markers were used to detect spinal cord alterations in SNI rats after chronic amylin administration.

Results:

Continuous subcutaneous amylin administration aggravated cold allodynia in SNI animals, possibly via amylin‐receptors (AmyR) in supraspinal areas. Acute intrathecal administration of amylin attenuated mechanical hyperalgesia, whereas AC187 reduced mechanical allodynia, suggesting distinct roles of endogenous amylin and of pharmacological amylin doses when targeting spinal cord amylin receptors. Chronic amylin administration promoted c‐Fos activation only in the dorsal horn neurons of SHAM animals, suggesting a distinctive role of amylin in the activation of the spinal neuronal circuitry under neuropathic and physiological conditions. ERK1/2 phosphorylation increased in the dorsal horn neurons of SNI rats chronically treated with amylin. This ERK1/2 cascade activation may be related to amylin's effect on the aggravation of cold allodynia in SNI rats.

Conclusions:

Amylin's nociceptive effects seem to depend on the treatment duration and route of administration by acting at different levels of the nervous system.

Significance:

Amylin modulated neuropathic pain by acting at different levels of the nervous system. Whereas supraspinal areas may be involved in amylin's induced pronociception, modulation of spinal cord amylin receptors by endogenous or pharmacological amylin doses triggers both pro‐ and antinociceptive effects.

01 Oct 2016·Molecular metabolismQ2 · MEDICINE

The satiating hormone amylin enhances neurogenesis in the area postrema of adult rats

Q2 · MEDICINE

ArticleOA

Author: Borner, Tito ; Liberini, Claudia G ; Lutz, Thomas A ; Boyle, Christina N

OBJECTIVE:

Adult neurogenesis in the subgranular zone and subventricular zone is generally accepted, but its existence in other brain areas is still controversial. Circumventricular organs, such as the area postrema (AP) have recently been described as potential neurogenic niches in the adult brain. The AP is the major site of action of the satiating hormone amylin. Amylin has been shown to promote the formation of neuronal projections originating from the AP in neonatal rodents but the role of amylin in adult neurogenesis remains unknown.

METHODS:

To test this, we first performed an RNA-sequencing of the AP of adult rats acutely injected with either amylin (20 μg/kg), amylin plus the amylin receptor antagonist AC187 (500 μg/kg) or vehicle. Second, animals were subcutaneously equipped with minipumps releasing either amylin (50 μg/kg/day) or vehicle for 3 weeks to assess cell proliferation and differentiation with the 5'-bromo-2-deoxyuridine (BrdU) technique.

RESULTS:

Acute amylin injections affected genes involved in pathways and processes that control adult neurogenesis. Amylin consistently upregulated NeuroD1 transcript and protein in the adult AP, and this effect was blocked by the co-administration of AC187. Further, chronic amylin treatment increased the number of newly proliferated AP-cells and significantly promoted their differentiation into neurons rather than astrocytes.

CONCLUSION:

Our findings revealed a novel role of the satiating hormone amylin in promoting neurogenesis in the AP of adult rats.

100 Deals associated with AC-187

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