Aceclidine

Abstract: A theoretical model is used to deduce the pharmacologically active conformation of acetylcholine and other agonists interacting with the muscarinic receptor of the parasympathetic and central nervous systems. This is accomplished by replacing the usual dihedral angles tau 1 and tau 2, which define the conformations of cholinergic drugs, with two new geometric parameters more suitable for describing the muscarinic pharmacophore: a characteristic distance, [PQ], and a dihedral angle, PNOQ. Values for these parameters are determined by conformational analysis on semirigid muscarinic agonists using molecular mechanics and ab initio molecular orbital methods. In addition to deducing the active conformation of acetylcholine and other agonists, the model also rationalizes the pattern of stereoselectivity in agonists related to 3-acetoxyquinuclidine (aceclidine) and furnishes a geometric criterion for partial agonism and antagonism.

Abstract: In primates, ciliary muscle contraction causes accommodation and facilitates aqueous outflow. In living rhesus monkeys, accommodative, outflow facility, and ciliary muscle movement responses to cholinergic agonists all decline with age. We developed an apparatus to determine in vitro whether the latter is related to intra- or extra-ciliary muscle factors, and whether ciliary muscle contraction in the coronal (putatively more accommodation-relevant) and longitudinal (putatively more facility-relevant) vectors can be dissociated pharmacologically. In fresh ciliary muscle strips, carbachol and aceclidine each induced dose-dependent contraction in the longitudinal and coronal vectors. With neither drug was there any apparent dissociation of the responses in the two vectors. Atropine pretreatment completely prevented a supramaximal dose of carbachol from inducing ciliary muscle contraction in either vector. Ciliary muscle strips responded to several cholinergic agonists as well on day 2 (24-32 hours post-enucleation) as on day 1 (1-9 hours post-enucleation) when kept in a cell culture medium at 4 degrees C. By light microscopy, the general architecture of the ciliary muscle, the muscle bundles, and the single muscle cells appeared normal; however, cellular and nuclear swelling were apparent following the 32-hour culturing period. Contractile responses to near-maximal doses of carbachol and aceclidine did not vary markedly with age in either vector, suggesting that the age-related decrease in ciliary muscle mobility in vivo is due to extra-muscular restrictive factors rather than diminished muscular contractility.

Abstract: Pirenzepine is thought to be a relatively selective cholinergic type I muscarinic antagonist1,2 and has been undergoing human U.S. Food and Drug Administration (FDA) clinical trials for the treatment of myopia (Siatkowski R, et al. IOVS 2003;45:ARVO E-Abstract 4778). It has been shown to prevent the development of form-deprivation myopia in chicks,3 tree shrews,4 and rhesus monkeys.5 In chicks, pirenzepine prevents form-deprivation myopia through a nonaccommodative mechanism,6 by preventing axial elongation through transient modulation of scleral glycosaminoglycan synthesis.7 Pirenzepine has a history of clinical use in the treatment of peptic ulcers as an inhibitor of gastric secretion and motility. It has been reported to cause ocular side effects, including accommodative difficulties.8 For the purposes of peptic ulcer treatment, pirenzepine is taken in 50-mg doses, twice daily by mouth. The concentration of pirenzepine used for the treatment of myopia in FDA clinical trials is substantially lower, but it is applied directly to the eyes in a gel formulation (Siatkowski R, et al. IOVS 2003;45:ARVO E-Abstract 4778). Therefore, some parasympathetic antagonistic ocular side effects may occur after administration of pirenzepine. In human FDA clinical trials, “blurred vision at near” was listed as one of three most common adverse events accounting for the 11% withdrawal rate (Siatkowski R, et al. IOVS 2003;45:ARVO E-Abstract 4778). A study in children with myopia showed that subjectively measured accommodative amplitude decreased 2 to 3 D compared with the placebo group after 1% and 2% pirenzepine gel instillation.9 Measurements were taken 60 minutes after instillation, and reduced amplitudes were present approximately 12 hours after instillation. The effect continued through month 9 of the 1-year study. Atropine, a nonselective muscarinic antagonist that has also been used for the treatment of myopia, causes ocular and systemic side effects due to its nonselective parasympathetic antagonism. Ocular side effects include mydriasis, leading to increased aberrations and photophobia,10 and paralysis of the ciliary muscle, leading to an inability to focus on near objects and the need for bifocal correction during treatment.11 It is believed that many of these side effects would be eliminated by using an M1-selective cholinergic antagonist such as pirenzepine at appropriate concentrations. Accommodation, the ability to change the focus of the eyes from distance to near, occurs after parasympathetic stimulation of the ciliary muscle. The human ciliary body and iris contain mainly M3-type receptors.12 Therefore, at concentrations for which pirenzepine is selective for M1 receptors, it is believed to have little effect on the ciliary muscle. In vitro, a continuous perfusion of 1.8 μM pirenzepine (0.07% solution) has been shown to inhibit contraction of the circular and longitudinal portions of the isolated rhesus monkey ciliary muscle stimulated by the muscarinic agonists carbachol, aceclidine, and oxotremorine.13 In vivo in rhesus monkeys, accommodation and pupil constriction elicited by pilocarpine are antagonized by continuous intracameral perfusion of 1.4 μM pirenzepine (0.059% solution),14 and responses elicited by aceclidine are antagonized by 7 μM pirenzepine (0.3% solution).16 At these relatively high concentrations, it is likely that pirenzepine acts through nonselective antagonism of the ciliary muscle through M3 receptors.13,14,15 Pirenzepine has been shown to reduce the progression of myopia in animal studies. In tree shrews, 7500 μg pirenzepine (i.e., 75 μL of 10% solution) injected subconjunctivally each day resulted in a significant reduction in form-deprivation myopia.4 In rhesus monkeys, a 5% pirenzepine solution delivered as 2 drops topically per day (approximately 5000 μg) was as effective as atropine at reducing the progression of form-deprivation myopia.5 In studies in chicks, intravitreal and subconjunctival injections of 0.0035 to 7500 μg have been used,17–19 and an ED50 for reducing myopia was achieved with subconjunctival injection of 5000 μg pirenzepine.18 It is of interest to determine what effects pirenzepine has on objectively measured accommodation at concentrations similar to those shown to be effective at reducing the progression of myopia in animals. Although there have been several studies on the use of pirenzepine for the treatment of myopia, there have been no published studies specifically exploring the effects of pirenzepine on objectively measured accommodation in humans or monkeys. For this reason, in the present study, the effects on accommodation of 0.2 mL of subconjunctivally injected 2% pirenzepine (i.e., 4000 μg), as well as lower concentrations, were studied. Although it was expected that 0.2 mL of 2% would result in nonspecific muscarinic effects, 4000 μg pirenzepine is comparable to, and indeed in many cases lower than, the amount shown to be effective at reducing the progression of myopia in animals. Because of the expected non-specificity of 2% pirenzepine, and because of the profound effects on accommodation (see results), after the 2% concentration was tested, additional testing of log unit dilutions, guided by studies in other tissues2 was undertaken to determine the pirenzepine concentrations at which accommodation would not be affected. This study was conducted in rhesus monkeys because they have high accommodative amplitudes20–22 and an accommodative mechanism23 and anatomy24 similar to that of humans. Accommodation in rhesus monkeys can be stimulated, rigorously controlled, and studied with objective methods to understand the effects of drugs on the ciliary muscle.23,25–29 In this study, the effects of pirenzepine—in concentrations similar to and lower than those shown to be effective at reducing the progression of myopia in animal models—on pupil size, resting refraction, and pharmacologically and centrally stimulated accommodative amplitude and dynamics were examined in rhesus monkeys.

Abstract: The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.