Muscarinic agonist SAR of azaspirodioxolanes

Shapiro, Gideon; Amstutz, René; Boddeke, Hendrikus; Bolliger, G.; Cottens, Sylvain; Enz, Albert; Gmelin, G.; Gull, P.; Supavilai, Porntip

doi:10.1016/s0960-894x(00)80537-5

Cited by 6 publications

(2 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Again the small methyl moiety at the acetalic position is optimal and necessary for muscarinic agonist activity. Bulkier substituents at this position cause a drop in agonist activity [31]. The small substituent at the acetalic position (CH 3 ) together with the pyrrolidine substructure (24) or the distorted piperidine ring (25) are responsible for the muscarinic receptor selectivity.…”

Section: Nmda Receptor Affinity Ki (Nm) [ 3 H]-tcp (A) or [ 3 H]-mk-mentioning

confidence: 99%

Relationships Between the Structure of Dexoxadrol and Etoxadrol Analogues and their NMDA Receptor Affinity

Sax¹,

Wünsch²

2006

CTMC

View full text Add to dashboard Cite

In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.

show abstract

Section: Nmda Receptor Affinity Ki (Nm) [ 3 H]-tcp (A) or [ 3 H]-mk-mentioning

confidence: 99%

Relationships Between the Structure of Dexoxadrol and Etoxadrol Analogues and their NMDA Receptor Affinity

Sax¹,

Wünsch²

2006

CTMC

View full text Add to dashboard Cite

show abstract

“…Much discussion has centered on the nature of the muscarinic agonist binding site. Some investigators 29 have proposed that the binding site is located in a very tight pocket with little tolerance for excess volume. Greater steric bulk is thought to lead to loss in agonist potency or a shift toward antagonism.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Pharmacological Characterization of O-Alkynyloximes of Tropinone and N-Methylpiperidinone as Muscarinic Agonists

1998

J. Med. Chem.

View full text Add to dashboard Cite

A number of O-alkynyloximes of tropinone and N-methyl-4-piperidinone have been synthesized and evaluated for muscarinic activity. The affinities of these oximes were tested in homogenates of cerebral cortex, heart, and submandibulary glands from rats using [3H]pirenzepine and [3H]-N-methylscopolamine as radioligands. The oximes bind to the cortical muscarinic receptors with pKi values varying from 3 to 7. Higher binding affinities were observed for the O-alkynyl tropinone oximes than the corresponding piperidinone analogues. Binding to the muscarinic sites in the heart and submandibulary glands was also observed but with lower affinities. Good M1 subtype selectivity (10-fold or greater) was observed with some oximes (26a, 28a, 32a) at the cortical sites. These oximes also attenuated scopolamine-induced impairment of the water mask task in mice. Functional assays for M3 activity on the rat aorta showed that all oximes possessed M3 agonist action but M2 agonist activity was not observed at the endothelium-denuded rabbit aorta. Analysis of the quantitative structure-activity relationship (QSAR) indicated that the Connolly surface area is an important determinant of activity, accounting for 70% of the variation in cortical binding affinity among the oximes.

show abstract

Reduced Flexibility Analogs of Analgesic and Cognition Enhancing α‐Tropanyl Esters

Manetti

Romanelli

Bartolini

et al. 1996

Archiv der Pharmazie

View full text Add to dashboard Cite

A series of semirigid analogs of compounds 1 and 2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg 22 is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5-HT4 antagonist SDZ 205557, the possible role of this receptor is discussed.

show abstract

Muscarinic agonist SAR of azaspirodioxolanes

Cited by 6 publications

References 8 publications

Relationships Between the Structure of Dexoxadrol and Etoxadrol Analogues and their NMDA Receptor Affinity

Relationships Between the Structure of Dexoxadrol and Etoxadrol Analogues and their NMDA Receptor Affinity

Synthesis and Pharmacological Characterization of O-Alkynyloximes of Tropinone and N-Methylpiperidinone as Muscarinic Agonists

Reduced Flexibility Analogs of Analgesic and Cognition Enhancing α‐Tropanyl Esters

Contact Info

Product

Resources

About