Abstract
The pharmacological profile of the γ-aminobutyric acid (GABA)B receptor regulating cholinergic twitch contraction in the guinea pig ileum myenteric plexus-longitudinal muscle preparation was investigated. GABA and (−)-baclofen inhibited the contraction, exhibiting quite close potencies (pD2 for GABA = 5.70; pD2 for (−)-baclofen = 5.33). The compound CGP 47656 also reduced the cholinergic twitch concentration (pD2 = 5.42), but its efficacy was significantly lower than that of (−)-baclofen or GABA. Added at varying concentrations, CGP 47656 modified the concentration-response curve of (−)-baclofen as expected for a partial agonist. Phaclofen, CGP 36742, CGP 35348, and CGP 52432 behaved as competitive antagonists of (−)-baclofen, exhibiting the following pA2 values: 3.90, 4.88, 5.02, and 7.82, respectively. The compound CGP 56999 behaved as a potent noncompetitive GABAB receptor antagonist. In comparing the pharmacological profile of the ileal receptor with those of the previously characterized pharmacological subtypes of the GABAB receptor present in the central nervous system, it can be seen that the GABAB receptor inhibiting cholinergic twitch contraction in guinea pig ileum myenteric plexus-longitudinal muscle mostly resembles the receptor located on somatostatin human neocortex nerve terminals.
Footnotes
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Send reprint requests to: Dr. Manuela Marcoli, Dipartimento di Medicina Sperimentale, Sezione Farmacologia e Tossicologia, Viale Cembrano 4-16148 Genova, Italy. E-mail:marcoli{at}pharmatox.unige.it
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↵1 This work was supported by an Italian MURST Network grant (1997).
- Abbreviations:
- GABA
- γ-aminobutyric acid
- CNS
- central nervous system
- CGP 35348
- 3-aminopropyl(diethoxymethyl)phosphinic acid
- CGP 36742
- 3-aminopropyl-n butyl phosphinic acid
- CGP 47656
- 3-aminopropyl-(difluoromethyl)phosphinic acid
- CGP 52432
- [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid
- CGP 56999
- [3{[1-(R)-(3-carboxyphenyl)ethyl]amino}-2-(S)-hydroxy-propyl]cyclohexyl-methyl-phosphinic acid
- MP-LM
- myenteric plexus-longitudinal muscle
- SRIF
- somatostatin
- CCK
- cholecystokinin
- Received October 21, 1999.
- Accepted January 6, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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