GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects

In the mid seventies a drug design programme using the Amanita muscaria con stituent muscimol (7) as a lead structure, led to the design of guvacine (2 3) and (R)-nipecotic acid (24) as specific GABA uptake inhibitors and the i someric compounds isoguvacine (10) and isonipecotic acid (11) as specific G ABA(A) receptor agonists. The availability of these compounds made it possi ble to study the pharmacology of the GABA uptake systems and the GABA(A) re ceptors separately. Based on extensive cellular and molecular pharmacologic al studies using 23, 24, and a number of mono- and bicyclic analogues, it h as been demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as phar macological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective bloc kade of neuronal as well as glial GABA uptake in order to enhance the inhib itory effects of synaptically released GABA, or (2) selective blockade of g lial GABA uptake in order to increase the amount of GABA taken up into, and subsequently released from, nerve terminals. The bicyclic compound (R)-N-M e-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 elucida tion of the pharmacology of GABA transporters. In recent years, a variety o f lipophilic analogues of the amino acids 23 and 24 have been developed, an d one of these compounds, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now market ed as an antiepileptic agent.