title: m-Azido-phencyclidine covalently labels the rat brain PCP receptor, a putative K channel.
abstract: Phencyclidine (PCP) is a schizophrenomimetic drug of abuse. PCP binds with high affinity (apparent dissociation constant, KD less than 10(-6) M) to rat brain membranes and blocks, selectively, a voltage-gated, noninactivating K channel found in rat brain synaptosomes (presynaptic nerve terminals). Thus, it has been proposed that the high-affinity PCP receptor in brain is this K channel. Consistent with this hypothesis, we now show that several K channel blockers displace 3H-PCP from the rat brain receptor. Additionally, we have used a photolabile analog of PCP, m-azido-PCP (Az-PCP), to identify the brain PCP receptor/putative K channel. In the dark, Az-PCP bound reversibly to 2 classes of sites on rat brain synaptic membranes [KD = 0.14 +/- 0.01 microM (n = 5) for high-affinity binding, and KD = 255 +/- 55 microM for low-affinity binding]. Competitive binding studies between Az-3H-PCP and nonlabeled PCP analogs, and between Az-PCP and several tritiated PCP analogs, indicated that the high-affinity Az-PCP binding site is the high-affinity PCP receptor. Several amino-pyridines (APs) and tetraalkylamines (TAAs), which are known to block K channels in excitable cells, were also found to displace 3H-PCP from its high-affinity binding site on rat brain synaptic membranes. The rank order of potency for displacement of 3H-PCP from this site for the APs was 4-AP approximately equal to 3,4-diAP greater than 2-AP much greater than 3-AP; for the TAAs it was TBA greater than TEA much greater than TMA (the tetra-butyl, ethyl, and methyl amines, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D015761:4-Aminopyridine; D000345:Affinity Labels; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D008970:Molecular Weight; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D010777:Photochemistry; D011188:Potassium / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine
chemical_list: C040647:3-azidophencyclidine; D000345:Affinity Labels; D000631:Aminopyridines; D001386:Azides; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D015761:4-Aminopyridine; C009405:tetrabutylammonium; D010622:Phencyclidine; D011188:Potassium