![]() Though the most common mechanism is simple competition, antagonism can occur in a variety of ways.ġ.5.1.1 Mechanisms Not Involving the Agonist Receptor Macromoleculeġ. Many of the most useful drugs are antagonists: substances that reduce the action of another agent, which is often an endogenous agonist (e.g., a hormone or neurotransmitter). Actually the cocaine antagonist AHN 2-005 is currently under development as a potential medication for ADHD. In addition, such studies would also contribute to identification of medications for attention-deficit hyperactivity disorder (ADHD) with lower potential of abuse since the typical dopamine uptake inhibitor methylphenidate (Ritalin ®) is currently prescribed for ADHD patients. ![]() Nonetheless, future studies on a cocaine-antagonist action should result in development of medications for cocaine abuse. Thus it is likely that a cocaine-antagonist action can be generated from several pathways and there might be no uniform pathway to induce a cocaine-antagonist action. In summary, none of these hypotheses uniformly explained the cocaine-antagonist action. Therefore the conformational differences in DAT are again not prerequisite for induction of a cocaine-antagonist action, either. Further, as with JHW 007, the standard dopamine uptake inhibitor GBR 12909 was found to bind the inward-facing conformation. However, as with cocaine, it was shown that the cocaine antagonist RTI-371 and the standard dopamine uptake inhibitor RTI-336 both bind the outward-facing conformation of the DAT. Thus binding to the inward-facing conformation appeared to be important for a cocaine-antagonist action. Studies evaluating accessibility of the sulfhydryl-reactive reagent -methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular DAT gate is open but inaccessible when it is closed, indicated that cocaine and its analogue WIN 35,428 bind an open DAT conformation to synapse clefts (outward-facing conformation), whereas several atypical dopamine uptake inhibitors (AHN 2-005, and JHW 007) bind a closed conformation (inward-facing conformation). There are several relatively viable mechanisms underlying their cocaine-antagonist effect.Ĭonformational Differences in DAT Binding An excellent review article recently discussed potential mechanisms underlying their action as a cocaine antagonist. However, the pattern of substitution was different from that of methadone since methadone can substitute for heroin or d-methamphetamine. On the other hand, none of them maintained self-administration responding above vehicle levels when substituted cocaine, d-methamphetamine, heroin or ketamine. ![]() ![]() The pattern of antagonism was similar to effects of the μ-opioid agonist methadone on heroin self-administration since methadone can also produce a dose-dependent insurmountable antagonism of heroin self-administration. ![]() Their dose-dependent insurmountable antagonism of cocaine self-administration was relatively specific because comparable responding maintained by presentations of food pellets was insensitive to active doses of these compounds that decreased maximal responding maintained by cocaine injection. Rimcazole, 9-9H-carbazole SH 3-24, -1-piperazinyl)-propyl]diphenylamine SH 3-28, 9-1-piperazinyl)-propyl]carbazole. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |