Have you seen what the moledules Hup A and donepezil look like? You can't guess at receptor binding based on a few similar functional groups in drastically different configurations. That is in NO WAY how structure-activity relationship works.
There is information about which drugs bind to which sigma receptors all over the internet (including this paper that's been posted in two threads). There's nothing for Hup A because it doesn't bind to sigma-1. If I'm wrong, find me a paper. Not hearsay.
Good points I will do my best, I have seen what they look like donepezil is a protypical sigma-1 agonist mainly because 3,4dimethyloxyphenyl, sigma-2 requires only one methyl oxy to be present.
The polyamine site on the NMDA recetpor represents an insertion of the adaptins sigma and maybe all the opoid aswell.THis quote maybe shows some indication.
The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes sources from"A new approach to the design of sigma-2-selective ligands: synthesis and evaluation of N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine-related polyamines at sigma-1 and sigma-2 receptor subtypes."
Then from your post "From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites"
The cholinergic system, sigma-1 receptors and cognition.
Abstract
This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole)(ANTAGONIST), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of beta-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.
SA4503 elicited the increase in extracellular acetylcholine level in rat frontal cortex, while it did not affect the striatal acetylcholine level. On the other hand, tetrahydroaminoacridine (THA), an acetylcholinesterase (AChE) inhibitor, increased the extracellular acetylcholine level in both regions. Although both compounds had anti-amnesic effect against scopolamine-induced memory impairment, THA also induced catalepsy in rats(ACETYLCHOLING IN THE STRATIUM CAUSE SOLELY THETA WAVES,WHICH ARE INCOMPATABLE WITH MOVEMENT)
Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil(SIGMA 1 ANTAGONTISUM OF NMDA I THINK IS TIME DEPENDENT, TAKES 6 HOURS TO TAKE EFFECT).
I have obviously comeup with very little hard evidence, but have highlighted information that points to me being correct
Edited by haha, 25 April 2010 - 07:07 AM.
