GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects
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GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects. / Krogsgaard-Larsen, P; Frølund, B; Frydenvang, Karla Andrea.
In: Current Pharmaceutical Design, Vol. 6, No. 12, 2000, p. 1193-209.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects
AU - Krogsgaard-Larsen, P
AU - Frølund, B
AU - Frydenvang, Karla Andrea
PY - 2000
Y1 - 2000
N2 - In the mid seventies a drug design programme using the Amanita muscaria constituent muscimol (7) as a lead structure, led to the design of guvacine (23) and (R)-nipecotic acid (24) as specific GABA uptake inhibitors and the isomeric compounds isoguvacine (10) and isonipecotic acid (11) as specific GABAA receptor agonists. The availability of these compounds made it possible to study the pharmacology of the GABA uptake systems and the GABAA receptors separately. Based on extensive cellular and molecular pharmacological studies using 23, 24, and a number of mono- and bicyclic analogues, it has been demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as pharmacological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective blockade of neuronal as well as glial GABA uptake in order to enhance the inhibitory effects of synaptically released GABA, or (2) selective blockade of glial GABA uptake in order to increase the amount of GABA taken up into, and subsequently released from, nerve terminals. The bicyclic compound (R)-N-Me-exo-THPO (17) has recently been reported as the most selective glial GABA uptake inhibitor so far known and may be a useful tool for further elucidation of the pharmacology of GABA transporters. In recent years, a variety of lipophilic analogues of the amino acids 23 and 24 have been developed, and one of these compounds, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now marketed as an antiepileptic agent.
AB - In the mid seventies a drug design programme using the Amanita muscaria constituent muscimol (7) as a lead structure, led to the design of guvacine (23) and (R)-nipecotic acid (24) as specific GABA uptake inhibitors and the isomeric compounds isoguvacine (10) and isonipecotic acid (11) as specific GABAA receptor agonists. The availability of these compounds made it possible to study the pharmacology of the GABA uptake systems and the GABAA receptors separately. Based on extensive cellular and molecular pharmacological studies using 23, 24, and a number of mono- and bicyclic analogues, it has been demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as pharmacological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective blockade of neuronal as well as glial GABA uptake in order to enhance the inhibitory effects of synaptically released GABA, or (2) selective blockade of glial GABA uptake in order to increase the amount of GABA taken up into, and subsequently released from, nerve terminals. The bicyclic compound (R)-N-Me-exo-THPO (17) has recently been reported as the most selective glial GABA uptake inhibitor so far known and may be a useful tool for further elucidation of the pharmacology of GABA transporters. In recent years, a variety of lipophilic analogues of the amino acids 23 and 24 have been developed, and one of these compounds, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now marketed as an antiepileptic agent.
KW - Animals
KW - Anticonvulsants
KW - Behavior, Animal
KW - Blood-Brain Barrier
KW - Drug Design
KW - Humans
KW - Neurotransmitter Uptake Inhibitors
KW - Nicotinic Acids
KW - Nipecotic Acids
KW - Prodrugs
KW - Proline
KW - Structure-Activity Relationship
KW - gamma-Aminobutyric Acid
M3 - Journal article
C2 - 10903390
VL - 6
SP - 1193
EP - 1209
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
SN - 1381-6128
IS - 12
ER -
ID: 40372251