ANALOGS OF CARBACHOLINE - SYNTHESIS AND RELATIONSHIP BETWEEN STRUCTURE AND AFFINITY FOR MUSCARINIC AND NICOTINIC ACETYLCHOLINE-RECEPTORS

A series of acyclic and heterocyclic analogues of carbacholine (1) was synthesized using N-methylcarbacholine (MCC, 2), N,N-dimethylcarbacho line (DMCC, 3), and the corresponding tertiary amine (4) as leads. Whe reas nicotinic acetylcholine receptor affinity was determined using [H -3]nicotine as the radioactive ligand, [H-3]oxotermorine-M ([H-3] Oxo- M) and [H-3]quinuclidinyl benzilate ([H-3]QNB), in come cases suppleme nted with [H-3]pirenzepine ([H-3]PZ), were used as radioligands for mu scarinic acetylcholine receptors on rat brain membranes. On the basis of receptor binding data, nicotinic/muscarinic (N/M) selectivity facto rs were determined, and muscarinic receptor efficacy (M agonist index) and M(1) selectivity (M(2)/M(1) index) estimated. In most cases, quat ernized analogues showed higher affinity that the corresponding tertia ry amines for muscarinic and, in particular, nicotinic receptor sites. Among the new compounds, N,N-diethylcarbacholine (9e) (IC50 = 0.046 m u M), 2-(N,N-dimethyl-aminocarbonyloxymethyl)pyrrolidine (17K) (IC50 = 0.068 mu M), and the corresponding quaternized analogue, 18K (IC50 = 0.018 mu M) showed the highest nicotinic receptor affinity. The tertia ry amine, 17k showed much higher nicotinic receptor affinity than the acyclic analogue, 4 (IC50 = 5.7 mu M), and the N/M selectivity factor determined for 17k (150) is an order of magnitude lower than that of n icotine (1400). The N/M selectivity factors for MCC (2) and DMCC (3), previously reported to be highly selective nicotinic receptor ligands, were shown to be 6.5 and 60, respectively, the latter value being com parable with that of 18k (89).