Involvement of the sigma1 (sigma1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41.

Abstract

BACKGROUND AND PURPOSE:

Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma(1) (sigma (1)) receptor ligand. The sigma (1) receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant DRUGS. WE HAVE HERE ANALYSED THE SIGMA (1) COMPONENT IN THE BEHAVIOURAL EFFECTS OF ANAVEX1-41.

EXPERIMENTAL APPROACH:

Binding of ANAVEX1-41 to muscarinic and sigma (1) receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures.

KEY RESULTS:

In vitro, ANAVEX1-41 was a potent muscarinic (M(1)>M(3), M(4)>M(2) with K(i) ranging from 18 to 114 nM) and selective sigma (1) ligand (sigma (1), K(i)=44 nM; sigma (2), K(i)=4 microM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg(-1)), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg(-1)). The sigma (1) antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a sigma (1) receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg(-1), without involving the sigma (1) receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide.

CONCLUSIONS AND IMPLICATIONS:

ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and sigma (1) receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes.

• Authors: J Espallergues, P Lapalud, A Christopoulos, V A Avlani, P M Sexton, A Vamvakides, T Maurice
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 2 Pg. 267-79 (Sep 2007) ISSN: 0007-1188 [Print] England
• PMID: 17641675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents
• Furans
• Muscarinic Antagonists
• Oligodeoxyribonucleotides, Antisense
• Receptors, Muscarinic
• Receptors, sigma
• sigma-1 receptor
• tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride
• Scopolamine

Topics

• Amnesia (drug therapy, metabolism, physiopathology)
• Animals
• Antidepressive Agents (pharmacology, therapeutic use)
• CHO Cells
• Cerebral Cortex (metabolism)
• Cricetinae
• Cricetulus
• Furans (pharmacology, therapeutic use)
• Humans
• Jurkat Cells
• Memory (drug effects)
• Mice
• Motor Activity (drug effects)
• Muscarinic Antagonists (pharmacology)
• Oligodeoxyribonucleotides, Antisense (pharmacology)
• Rats
• Receptors, Muscarinic (metabolism)
• Receptors, sigma (metabolism)
• Scopolamine (pharmacology)
• Swimming