Structure−Affinity Relationships of a Unique Nicotinic Ligand:  N-Dimethyl-N⁴-phenylpiperazinium Iodide (DMPP)

Abstract

DMPP is a well-known nicotinic agonist that does not fit any proposed pharmacophore for nicotinic binding and represents a unique ligand among the hundreds of nicotinic agonists studied in the past decades. A systematic modulation of the chemical structure of DMPP, aimed to establish its structure-affinity relationships, is reported. The research has allowed to identify molecules such as 11c, 13c, 14c, and 28c, with affinities for alpha(4)beta(2) receptors in the low nanomolar range, some 2 orders of magnitude lower than the lead compound. The agonistic properties of the most interesting compounds have been assessed by measuring their analgesic activity on mice (hot-plate test). Another result of the research was the identification of DMPP analogues, such as 3a (K(i) = 90 nM) and 14b (K(i) = 180 nM), that maintain affinity for the central nicotinic receptor when the ammonium function is changed into an aminic one and are therefore possible leads for drug development in neurodegenerative diseases.

Design, synthesis and binding affinity of new nicotinic ligands

“…To check whether these compounds behave as agonists, the analgesic activity of the most active substances was measured by means of the hot-plate test on mice (Figure 1). 50,58 All the tested compounds, when injected intracerebroventricularly (i.c.v. ), are able to induce an analgesic effect which is completely prevented by mecamylamine at the dose of 5 mg/kg i.p.…”

Design, synthesis and preliminary pharmacological evaluation of rigid analogues of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)

“…23 [ 3 H]-Cytisine was used as radioligand; this compound is reported to label the α4β2 subtype, which is believed to represent up to 90% of the high affinity agonist binding site in the brain. 32 33 Among the frozen analogues of DMPP and of 3-pyridylpiperazine (compounds 2a-c, 4a-c, 3a and 3b), only methiodide 2c shows affinity for the central nicotinic receptor with K i 2.02 µM (confidence limits 1.24-3.29 µM); the other compounds do not displace [ 3 H]-cytisine from rat cerebral cortex up to a 100 µM concentration.…”

“…23 On the contrary, it seems that the freezing of the phenylpiperazinium moiety into a tricyclic structure is detrimental for activity, since the methiodide 4c does not interact with the receptor, and the affinity of compound 2c is 8-fold lower than that of DMPP. The lack of affinity of the aza compounds 3a and 3b is also unexpected, since the parent compounds 1a and 1b show K i values in the nanomolar range.…”

“…In fact, 2c (K i 2.02 µM) and 4c (Ki > 100 µM), differing for the double/single bond within the indole ring, show a difference in their volume of 4.58 Å 3 . In this respect, it must be noticed that also 1,1,3-trimethyl-4-phenylpiperazinium iodide (the 3-methyl analogue of DMPP) 23 is completely devoid of affinity. In addition, the reduction of the indole double bond, while reducing the surface of the aromatic part, induces a bending in the molecule (Figure 3) which may not be compatible with the space available at the binding site.…”

“…[15][16][17][18][19][20] The nicotinic pharmacophore is formed by two groups: an H-bond acceptor atom, usually a pyridyl nitrogen or a carbonyl oxygen, and a positive nitrogen, which can be protonated or quaternarized; the proposed distance between these two groups ranges from 4.5 Å 15 to 5.5 Å. 16,21 As a part of our research in the field of nicotinic ligands, we have recently reported the synthesis and pharmacological evaluation of a series of analogues of 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) 22,23 (general formula A, Figure 1 A well-known nicotinic agonist which, lacking the H-bond acceptor group, does not fit the proposed nicotinic pharmacophore. DMPP is reported to bind to the central nicotinic receptor with K i values ranging from 57 nM 24 to 250 nM; 22 it has been shown 23 that the introduction of substituents on the phenyl ring greatly improved affinity but in general, derivatives with a permanent positive charge showed higher potency than their tertiary amino analogues.…”