Biomaterial Database

Affinity ligands and related agents for brain muscarinic and nicotinic cholinergic receptors. 1993

L G Abood, and M Saraswati, and N Lerner-Marmarosh, and M Hashmi

Department of Pharmacology, University of Rochester Medical Center, NY 14642.

This study describes the chemical synthesis and receptor binding characteristics of various affinity ligands and related ligands for brain muscarinic and nicotinic cholinergic receptors, including the 4-bromoacetamidobenzoic acid esters of dimethylaminoethanol (DMBAB) and choline (BABC) and 4-iodoacetamidobenzoylcholine (IABC). The reversible binding of [3H]3-quinuclidinylbenzilate ([3H]QNB) to calf brain membranes was inhibited in a concentration-dependent and saturable manner by DMBAB, BABC, and IABC with Ki values of 8 x 10(-7), 3 x 10(-7) and 8 x 10(-7) M, respectively; the Ki values for inhibition of reversible binding of the nicotinic ligand, [3H]methylcarbamylcholine ([3H]-MCC), were 1 x 10(-6), 6 x 10(-8), and 1 x 10(-6) M, respectively. The Ki values for irreversible inhibition of [3H]QNB binding were 8 x 10(-7), 1 x 10(-7), and 2 x 10(-7) M for DMBAB, BABC, and IABC, respectively, and for [3H]MCC binding, 8 x 10(-5), 1 x 10(-5), and 2 x 10(-5) M, respectively. Although DMBAB was found to inhibit the QNB-induced hyperactivity in mice, it did not antagonize the toxic or other pharmacologic effects of oxotremorine. Structure-activity studies with various non-affinity analogues of the 4-aminobenzoate ester of dimethylaminoethanol and choline revealed that removal of the NH2 moiety from the phenyl group increased affinity for the muscarinic but not the nicotinic cholinergic site, and quaternization of the ester side chain greatly increased affinity for the muscarinic site. Dimethylation of NH2 in 4-aminobenzoylcholine decreased the affinity for both cholinergic sites. Replacement of NH2 by NO2 increased affinity for the muscarinic but not the nicotinic site, whereas quaternization of the 4-nitrobenzoyl ester markedly increased affinity for the nicotinic site while diminishing affinity for the muscarinic site. The findings indicate that DMBAB and its analogues are useful affinity ligands for examining the biochemical and functional characteristics of brain cholinergic receptors, particularly the muscarinic which has an affinity near the nanomolar concentration range.

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D009270	Naloxone	A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors.	MRZ 2593-Br,MRZ-2593,Nalone,Naloxon Curamed,Naloxon-Ratiopharm,Naloxone Abello,Naloxone Hydrobromide,Naloxone Hydrochloride,Naloxone Hydrochloride Dihydride,Naloxone Hydrochloride, (5 beta,9 alpha,13 alpha,14 alpha)-Isomer,Naloxone, (5 beta,9 alpha,13 alpha,14 alpha)-Isomer,Narcan,Narcanti,Abello, Naloxone,Curamed, Naloxon,Dihydride, Naloxone Hydrochloride,Hydrobromide, Naloxone,Hydrochloride Dihydride, Naloxone,Hydrochloride, Naloxone,MRZ 2593,MRZ 2593 Br,MRZ 2593Br,MRZ2593,Naloxon Ratiopharm
D009538	Nicotine	Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke.	Nicotine Bitartrate,Nicotine Tartrate
D010095	Oxotremorine	A non-hydrolyzed muscarinic agonist used as a research tool.	Oxytremorine
D011343	Procaine	A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016).	Anuject,Geriocaine,Gerokit,Hewedolor-Procain,Lophakomp-Procain N,Novocain,Novocaine,Procain Braun,Procain Jenapharm,Procain Rödler,Procain Steigerwald,Procain curasan,Procaina Serra,Procaine Hydrochloride,Pröcaine chlorhydrate Lavoisier,Röwo Procain,procain-loges,Hydrochloride, Procaine
D011813	Quinuclidinyl Benzilate	A high-affinity muscarinic antagonist commonly used as a tool in animal and tissue studies.	Benzilate, Quinuclidinyl
D011976	Receptors, Muscarinic	One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for MUSCARINE over NICOTINE. There are several subtypes (usually M1, M2, M3....) that are characterized by their cellular actions, pharmacology, and molecular biology.	Muscarinic Acetylcholine Receptors,Muscarinic Receptors,Muscarinic Acetylcholine Receptor,Muscarinic Receptor,Acetylcholine Receptor, Muscarinic,Acetylcholine Receptors, Muscarinic,Receptor, Muscarinic,Receptor, Muscarinic Acetylcholine,Receptors, Muscarinic Acetylcholine
D011978	Receptors, Nicotinic	One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for NICOTINE over MUSCARINE. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, and subunit composition of the receptors.	Nicotinic Acetylcholine Receptors,Nicotinic Receptors,Nicotinic Acetylcholine Receptor,Nicotinic Receptor,Acetylcholine Receptor, Nicotinic,Acetylcholine Receptors, Nicotinic,Receptor, Nicotinic,Receptor, Nicotinic Acetylcholine,Receptors, Nicotinic Acetylcholine
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon