Steric and electronic requirements for muscarinic receptor-stimulated phosphoinositide turnover in the CNS in a series of arecoline bioisosteres.
A series of arecoline derivatives was utilized to assess steric and electronic effects important for activating muscarinic receptors in the CNS. Arecoline derivatives in which the methyl ester moiety was replaced by hexyloxy-1,2,5-oxadiazole (2b), hexyloxythiophene (3b) or hexyloxypyrazine (4b) were compared with the hexyloxy-1,2,5-thiadiazole compound (1b) (Hexyloxy-TZTP), known from previous work to be active as an M1/M3 partial agonist. MNDO calculations showed that the N-S bonds of the alkoxythiadiazole ring were highly polarized with the ability to form H-bonds to the N's. On the other hand, the smaller oxadiazole had lower polarities in the N-O bonds and reduced ability to form H-bonds, the thiophene was of comparable size to the thiadiazole and had large C-S bond polarities without the H-bond capability and the pyrazine had limited ability to form H-bonds. The compounds were compared with respect to their abilities to stimulate phosphoinositide (Pl) turnover in the hippocampus of the rat brain. 1b was more active than 2b-4b for stimulating the Pl turnover response. The data suggest that the ability to form H-bonds is an important factor for the ability of 1 to stimulate M1 muscarinic receptors in the CNS.
Ngur
D
D
Department of Medicinal and Biological Chemistry, University of Toledo, Ohio 43606.
Roknich
S
S
Mitch
C H
CH
Quimby
S J
SJ
Ward
J S
JS
Merritt
L
L
Sauerberg
P
P
Messer
W S
WS
Hoss
W
W
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives / Q000494:pharmacology*; D001921:Brain / Q000502:physiology*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D001115:Arecoline