Current Medicinal Chemistry, 2002, 9, 1567-1589 1567 Non-peptide Opioid Receptor Ligands - Recent Advances. Part I - Agonists Agnieszka Kaczor* and Dariusz Matosiuk* Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University at Lublin, 6 Staszica Str., PL-20081 Lublin, Poland Abstract : Developments in the domain of non-peptide opioid receptor agonists, beginning from the first evidence of opiate binding to definite receptors, are briefly summarized. The recent achievements are in a more detailed way depicted and discussed. Novel agonists for each of three opioid receptor basic types (δ , κ and μ) are presented with the special emphasis on one-type-selective ligands. Such selective or even specific agonists have been synthesized with a moderate success. Considerably more serious difficulties concern searching for selective ligands for opioid receptor subtypes (μ 1 , μ 2 , δ 1 , δ 2 , κ 1 , κ 2 , κ 3 ) which may be connected with the fact that dissimiliarities observed in vivo result from postbinding processes (signaling). For the large number of opioid receptor ligands, their structural diversity and relative easiness of generating them from combinatorial libraries (not comparable even with that of orphanine receptors) it is justified to consider the plasticity of opioid receptors (μ-receptor especially). This remark, in conjunction with the existence of opioid receptor types and subtypes, may enable to create new drugs with significantly reduced side-effects. The above facts and brand new reports about highly-active opioid agonists possessing no moieties thought to be essential for agonist activity make the need of reevaluation of classical opioid receptor pharmacophore model extremely important. In general, research results suggest that selective agonists of opioid receptors can be found both in morphine type of ligands and new structures like pyrido-acridine derivatives (COMP1) or diphenylmethylpiperazine derivatives (SNC 80). Better understanding of the structural prerequisites of the opioid receptors binding domains will certainly lead to even more potent and more selective ligands in a near future. Key words: opioid receptors, non-peptide agonists, binding domain, pharmacophore models, morphine-like agonists, non- morphine-like agonists. 1. INTRODUCTION nalorphine enhanced biochemical research aimed to prove the opioid binding sites existence. In 1973 three laboratory teams demonstrated opioid binding to definite sites by application of tritium-labeled naloxone [4], tritium-labeled dihydromorphine [5] and tritium labeled etorphine [6]. The name of the basic opium alkaloid, morphine, takes its origin from the Greek god Morpheus, who used to send human-shaped dreams. It seems then understandable that morphine and relative natural alkaloids have been used as medicines for ages. The significant turn in the discovery of new drugs was the concept of receptor that was introduced over a hundred years ago by Fisher [1] and developed by Langley [2] and Ehrlich [3]. About forty years later Beckett and Casy while working on semisynthetic opioids set forth a hypothesis that opioids interact with specific parts of the receptors, that is binding sites. This supposition, in conjunction with successful synthesis of the opioid antagonist naloxone as well as the mixed agonist-antagonist It used to be thought that opioid receptors are a homogenic group. However, in 1976, the research performed by Martin and his co-workers showed the presence of three opioid receptor types. The terms for the receptors derive from the prototypic substance used for investigation: μ for morphine, κ for ketocycloazocine and σ for SKF 10047 (N- allilnormetazocine). This division is current in the case of first two receptors. The sigma receptor is not considered opioid one as naloxone does not block the effects of its activation. The discovery of endogenous peptides in 1975 led to description of one more opioid receptor type, called δ, as the research was carried out on isolated mouse vas deferens, where this receptor occurs on a large scale. *Address correspondence to these authors at the Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University at Lublin, 6 Staszica Str., PL-20081 Lublin, Poland; Phone: *048-81-532 29 10; Fax: *048-81-532 29 10; E-mail: darek@eskulap.am.lublin.pl At present three main types of opioid receptors - δ, κ and μ are distinguished. Orphan receptor is sometimes included 0929-8673/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd.