Delving into the Latest Updates on SORI-6238 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

SERT

Mechanism

SERT inhibitors(Serotonin transporter inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Nervous System Diseases

Originator Organization

Southern Research Institute

Active Organization-

Inactive Organization

RTI International Metals, Inc.

Southern Research Institute

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC16H15Cl2N5O2

InChIKeyRYXHPKXJBBAPCB-UHFFFAOYSA-N

CAS Registry82585-98-6

The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI-6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'.

100 Deals associated with SORI-6238

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