Adenosine analogs mediating depressant effects on synaptic transmission in rat hippocampus: Structure-activity relationships for the N6 subregion
- 1 September 1986
- journal article
- Published by Springer Science and Business Media LLC in Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie
- Vol. 334 (1), 77-85
- https://doi.org/10.1007/bf00498743
Abstract
Previous studies have shown that analogs of adenosine with substituents upon the N6-nitrogen (e.g., N6-[1-phenyl-2(R)-propyl]adenosine; R-PIA) are often much more potent than the parent compound in activating adenosine receptors, particulary those of the A1 subtype. The present investigation characterized the potencies of a number of N6-substituted adenosine analogs in depressing excitatory synaptic transmission in slices of rat hippocampus, an electrophysiological response mediated by receptors of the A1 subtype. These potencies correlated well with previously reported affinities of these analogs for A1 receptor sites in brain, but not with coronary vasodilation in the dog heart, an A2 receptor mediated response. Analogs with alkyl or aryl substituents at the N6 position were generally more potent than adenosine, although analogs with a tertiary carbon attached directly to the N6-nitrogen were usually only weakly active. Although it has been suggested that there may be a subregion of the A1 receptor with some specificity for aryl groups, these experiments did not suggest that this was the case. Analogs with chiral centers attached to the N6-nitrogen usually displayed stereoselectivity, with R-isomers more potent than the S-isomers. The mechanism underlying this selectivity appeared to be both a facilitating effect of alkyl substituents in the propyl C1 position of R-PIA, and a hindering effect of substituents in the position normally occupied by the hydrogen attached to propyl C2 of R-PIA. These results indicate that although there are some similarities in terms of requirements for activity at A1 and A2 receptors, differences between the N6 sub-regions of these receptors are sufficient to permit the development of selective analogs for these two receptor sites.Keywords
This publication has 28 references indexed in Scilit:
- Structure-activity relationships for N6-substituted adenosines at a brain A1-adenosine receptor with a comparison to an A2-adenosine receptor regulating coronary blood flowBiochemical Pharmacology, 1986
- The Physiological Role of Adenosine In The Central Nervous SystemInternational review of neurobiology, 1985
- Adenosine decreases aspartate and glutamate release from rat hippocampal slicesEuropean Journal of Pharmacology, 1984
- Interactions between the effects of adenosine and calcium on synaptic responses in rat hippocampus in vitro.The Journal of Physiology, 1984
- Adenosine receptors mediating inhibitory electrophysiological responses in rat hippocampus are different from receptors mediating cyclic AMP accumulationNaunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 1984
- Electrophysiological responses to adenosine analogs in rat hippocampus and cerebellum: Evidence for mediation by adenosine receptors of the A1 subtypeLife Sciences, 1984
- ADENINE NUCLEOTIDES AND SYNAPTIC TRANSMISSION IN THE in vitro RAT HIPPOCAMPUSBritish Journal of Pharmacology, 1980
- Long‐term potentiation and depression of synaptic responses in the rat hippocampus: localization and frequency dependency.The Journal of Physiology, 1978
- Presynaptic inhibitory actions of adenine nucleotides and adenosine on neurotransmission in the rat vas deferensNeuroscience, 1977
- Interhippocampal ImpulsesActa Physiologica Scandinavica, 1960