Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs.
The enantiomers of two alpha-tropanyl esters, SM21 (1) and PG9 (2), derived from (+)-R-hyoscyamine, that act by increasing the central cholinergic tone, were obtained by esterification after resolution of the corresponding racemic acids [(-)-S-1, (-)-R-2 and (+)-S-2] and by stereospecific synthesis [(+)-R-1]. Their analgesic and cognition-enhancing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselectivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the groups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM21, (+)-S-PG9]. The ACh-releasing effect of the enantiomers of SM21 in rats is in agreement with the results in mice, while PG9 enantiomers do not show any appreciable enantioselectivity in this test. On the basis of the different effects of the 5-HT4 antagonist SDZ 205557 on analgesia induced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the alpha-tropanyl ester of 2-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds.
Romanelli
M N
MN
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Bartolini
A
A
Bertucci
C
C
Dei
S
S
Ghelardini
C
C
Giovannini
M G
MG
Gualtieri
F
F
Pepeu
G
G
Scapecchi
S
S
Teodori
E
E
D000109:Acetylcholine / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000737:chemistry / Q000494:pharmacology; D001286:Atropine Derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004025:Dicyclomine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D017551:Microdialysis; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000700:Analgesics; D001286:Atropine Derivatives; D018697:Nootropic Agents; D010276:Parasympatholytics; D004025:Dicyclomine; D001285:Atropine; D000109:Acetylcholine