LOBELINE AND STRUCTURALLY SIMPLIFIED ANALOGS EXHIBIT DIFFERENTIAL AGONIST ACTIVITY AND SENSITIVITY TO ANTAGONIST BLOCKADE WHEN COMPARED TO NICOTINE

In the present study, lobeline and two structurally simplified analogs were evaluated for activity in muscarinic and nicotinic binding assay s, a functional assay for nicotinic receptor activation (Rb-86(+) effl ux from striatal synaptosomes) and an acetylcholinesterase (AChE) assa y. Lobeline displaced [H-3]cytisine binding to rat cortical membranes with a mean inhibition constant (K-I) value of 16.0 nM, while the lobe line analogs CRM-I-13-1 and CRM-I-32-1 exhibited values of 15.0 and 5. 4 mu M, respectively. [3H]methylscopolamine was displaced by lobeline with a mean K, value of 37.0 mu M while CRM-I-13-1 and CRM-I-32-1 exhi bited values of 55.0 and 16.0 mu M, respectively. While nicotine stimu lated Rb-86(+) efflux from striatal synaptosomes in a mecamylamine rev ersible manner at each concentration tested, lobeline slightly increas ed Rb-86(+) efflux at lower concentrations and reduced efflux at highe r concentrations. Further, none of the lobeline effects were reversed with mecamylamine. Although less potent, the two lobeline analogs exhi bited a similar pattern of activity. These data may suggest that lobel ine and structurally similar compounds bind with different subtype sel ectivity than nicotine, or exert their agonists effects through non-ni cotinic mechanisms. All of the compounds tested were at least several hundred times less potent than physostigmine as AChE inhibitors. While some differences were apparent between the lobeline analog which cont ained the 2-keto-ethyl portion of lobeline and the analog which contai ned the phenyl 2-hydroxy-ethyl moiety, each compound was much less act ive than lobeline in most parameters assessed. (C) 1998 Elsevier Scien ce Ltd. All rights reserved.