Synthesis and structural, conformational, biochemical, and pharmacological study of new compounds derived from tropane-3-spiro-4'(5')-imidazoline as potential 5-HT3 receptor antagonists.
A series of tropane-3-spiro-4'(5')-imidazolines was synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 2'-(1H-indol-3-yl)tropane-3-spiro-4'(5')-imidazoline hydrochloride 5(6)f was determined by X-ray diffraction. In CD3OD solution, compounds 5(6)a-f display the same preferred conformation. The pyrrolidine and piperidine rings adopt an envelope conformation flattened at N8 and a distorted chair conformation puckered at N8 and flattened at C3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. This conformation is similar to that observed for compound 5(6)f in the solid state. From binding studies on the compounds synthesized, compound 5(6)d demonstrated the ability to efficiently displace the binding of [3H]GR65630 to bovine brain area postrema membranes to an extent comparable to MDL 72222. In the von Bezold-Jarisch reflex, compound 5(6)d was equipotent with metoclopramide. It is, therefore, likely that the imidazoline ring may provide a useful bioisosteric replacement for the carbonyl group in 5-HT3 antagonists.
Whelan
B A
BA
Dto. de Química Orgánica, Universidad de Alcalá de Henares, Madrid, Spain.
Iriepa
I
I
Galvez
E
E
Orjales
A
A
Berisa
A
A
Labeaga
L
L
Garcia
A G
AG
Uceda
G
G
Sanz-Aparicio
J
J
Fonseca
I
I
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D002552:Cerebral Ventricles / Q000378:metabolism; D003460:Crystallization; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D051381:Rats; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D007093:Imidazoles; D007211:Indoles; D012702:Serotonin Antagonists; D013141:Spiro Compounds; C093111:tropane-3-spiro-4'(5')imidazoline; C059068:GR 65630